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THE CHEMISTRY OF SYNTHETIC DRUGS 



THE CHEMISTRY 

OF 

SYNTHETIC DRUGS 

Br 
PERCY MAY, D.Sc. (Lond.), F.I.C. 

SECOND EDITION, REVISED AND ENLARGED 



LONGMANS, GREEN AND CO. 
39 PATERNOSTER ROW, LONDON 

FOUKTH AVENUE & 30th STREET, NEW YORK 
BOUHAY, CALCUTTA, AND MADRAS 

■ais 

[All nghls rairttdi 



■J 






PREFACE TO SECOND REVISED 

EDITION 

As was stated in the Preface to the First Edition, this 
book contains an account of the main facts concerning 
the chemical nature of synthetic drugs and the guiding 
principles which are used in their production. New drugs 
are constantly being introduced, and though many of them 
are well known and widely used, their chemical nature is 
often unknown even to chemists possessing a good know- 
ledge of general organic chemistry. For this reason there 
appeared to be some need for an attempt to increase the 
interest of chemists in a branch of their subject which is 
very interesting in itself, and which also affords scope for 
commercial application. 

Before the war, the manufacture of synthetic drugs 
was practically confined to Germany, but since 1914 con- 
siderable progress has been made with their production 
in this country. The manufacture of synthetic organic 
chemicals on a large scale presents many difficult prob- 
lems, and it is gratifying to find that most of these have 
been successfully overcome by British chemists in so short 
a time, and working under such difficult conditions. 
Nevertheless, it will probably be necessary to give some 
form of protection to this important growing industry for 
some years after the conclusion of peace if it is to hold its 
own in competition with the vast and highly organized 
German organic chemical industry. 



364680 



vi PREFACE TO SECOND REVISED EDITION 

This book contains more than a mere description of 
the chemical nature and mode of preparation of many 
synthetic drugs. For a scientific understanding of the 
subject, it is necessary to pay considerable attention to 
reactions taking place between the drug and the living 
organism whenever these can be traced, and to the rela- 
tion between the chemical character of a substance and its 
pharmacological action, even though this relation is neither 
so complete nor so simple as might be desired, and is con- 
fined to only a few of the numerous chemical compounds 
that are utsed as drugs. 

It has been thought desirable to mention briefly the 
therapeutic effect of most of the chief drugs, so that readers 
may gain some idea of their relative importance, but no 
attempt has been made to deal in any detail with pharma- 
cology or therapeutics, subjects which lie quite outside the 
scope and aim of this book. It has been neither possible 
nor necessary to mention all the synthetic drugs which 
have been prepared in recent years, as many of them pos- 
sess neither scientific nor therapeutic value. 

Besides the practical importance and inherent interest 
of the subject, it may also be of great value as a means of 
opening up new channels of research and of discovering 
new types of compounds. Just as the discovery of the 
coal-tar colours gave a great stimulus to the study of 
aromatic compounds, so the efforts to produce new drugs 
have led to a greatly increased knowledge of certain types 
of compounds, as for example those containing carbon 
united to arsenic and antimony. 

Further, it is hoped that this volume may prove of 
interest to those medical men who desire to obtain more 
unbiassed information concerning the application of 
chemistry to therapeutics and pharmacology than can be 
obtained from the countless trade circulars with which 
they are, or used to be, inundated. 

The arrangement of the subject-matter invariably pre- 
sents difficulties in a book of this kind. No plan can be 



PREFACE TO SECOND REVISED EDITION vu 

entirely logical and satisfactory, but it is hoped that the 
arrangement here used will be found a convenient one. 
Cross references have been inserted wherever possible. 

I wish to express my thanks for the encouraging re- 
ception given to the first edition of this book, and especially 
to those readers who have been kind enough to point out 
omissions or errors. In addition to minor alterations, 
certain sections have been largely rewritten on account of 
recent developments of the subject, and some entirely new 
sections have been added. 

My most grateful thanks are due to Mr. H. W. Vernon 
for his help in correcting the proofs of this edition. 

P. M. 

May, 1918. 



CONTENTS 



PAGB 
Pbbfacb V 

List of Abbbbyiations zi 

Globsaby xii 

CHAPTER I 
Intboductioh — Thb Thbobt of thb Action of Synthetic Dbugs 1 

CHAPTER II 
The Effect of Vabious Elements and Radicles ... 16 

CHAPTER III 
Thb Chemical Changes of Dbugs in the Obganibm ... 36 

CHAPTER IV 
Nabcotics and Oenebal Anesthetics 44 

CHAPTER V 

Antipybetics and Analgesics. (Dbbivatiyes of Aniline and 
Phenylhydbazine) 63 

CHAPTER VI 
Alkaloids 78 

CHAPTER VII 

Atbopine and the Tbopeines— Cocaine and the Local Anibs- 
THETICS 86 

CHAPTER VIII 

MoBPHiNS Gboup and Isoquinoline Groups of Alkaloids . . 104 

ix 



w 



X CONTENTS 

CHAPTER IX PAGE 

Adbenalinb and Othbb Debivatiyes of Ethylahine . . . 129 

CHAPTER X 
Dbbivatives of Phenol (Antiseptics) 152 

CHAPTER XI 
Other Obganig Antiseptics, excluding Halogen Compounds . 170 

CHAPTER Xn 
Halogen Antibeftics and Other Halogen Compounds . . 179 

CHAPTER Xin 
Inqbganxc Antisbftics and Mbtallio Compounds .... 190 

CHAPTER XIV 
Arsenic and Antimony Compounds 197 

ft 

CHAPTER XV 
Purine Debivativxs (Diurbtigs) and Otser Uric Acid Sliminants 217 

CHAPTER XVI 

Purgatives and Ot^eb Substances Acting on the Gastro- 
intestinal Tract 225 

CHAPTER XVn 
Various Other Compounds op Interest 232 

Index 241 



( 



LIST OF ABBREVIATIONS 

USED FOR TITLES OF JOURNALS, ETC. 

A.e, P. P. — Archiv fiir ezperiznentelle Pathologie und Pharmakologie. 
Amer. Joum, Pharm, — American Journal of Pharmacy. 
Amer, Joum. Physiol, — American Journal of Physiology. 
Annalen, — Justus Liebig^s Annalen der Ghemie. 

A. Pharm. — Archiv der Pharmsbcie. 
Apoth, Ztg, — Apotheker-Zeitung. 

Beitr. Chem. Physiol. Path, — ^Hofmeister's Beitrage zur chemischen Phy- 

siologie und Pathologie. 
Ber. — Berichte der Deutschen oljiemischen Gesellschaft. 
Ber, hlin. W, — Berliner klinisc!he Woohenschrift. 
Bera, Jahresb. — Berzelius* Jahresbericht uber die Fortsohritte der Ghemie. 

B. M, J. — ^British Medical Journal. 

Bid, — Bulletin de la Soci^t^ chimique de Paris. 

Bull. Coll, Agr, Tokyo, — ^Bulletin of the GoUege of Agriculture, Imperial 
University, Tokyo. 

C. B, — Gomptes rendus hebdomadaires de TAcademie des Sciences. 

(Paris.) 
Chemik, Ztg, — Ghemiker-Zeitung. (Gothen.) 
BmU, med, W, — Deutsche medizinische Wochensohrift. 

D. B, P. — Deutsohes Reiohs Patent.* 

E. P.— British Patent. 

Fortschr. — ^Friedlander, Fortschritte der Teerfarbenfabrikation. 

J. C, S. — Journal oithe Ghdmicol Society (Lcmdon), Transactions. 

Joum, of Physiol. — Journal of Physiology. (London.) 

Joum. prakt, Chem. — Journal fiir praktische Ghemie. 

Merck*s Jahresb. — ^Merck's Jahresbericht. (Since 1894 an English edition 

has been published under the title " Merck's Annual Report.") 
MoncUsh, — Monatshefte fiir Ghemie und verwandte Theile anderer Wissen- 

schaften. (Sitzungsberichte der k^. Akademie zu Wien.) 
Monatsh. f. pr. Derm. — Monatshefte fur prsiktische Dermatologie. 
Milnchener med, W, — Milnchener medizinische Wochenschrift. 
PflUger^s Archiv. — Archiv fiir die gesammte Physiologic des Menschen und 

der Thiere, herausgegeben von E. F. W. Pfliiger. 
Pharm. Ztg, — Pharmazeutische Zeitung. 

Proc, Chem. 8oc. — Proceedings of the Ghetaical Society. (London.) 
Proc, Amer. Physiol. Soc, — Proceedings of the American Physiological 

Society. 
Proc, Roy. Soe, — Proceedings of the Royal Society. (London.) 
Proc Boy. Soc, Edinb^ — Proceedings of the Royal Society of Edinburgh. 
Proc, Boy, Soc. Med. — Proceedings of the Royal Society of Medicine. 

(London.) 
Bee. Trav. Chim, — ^Receuil des travaux chimiques des Pays-Bas et de la 

Belgique. 
Trans. Boy. Soc. Ed. — Transactions of the Royal Society of Edinburgh. 
U. S. P. — ^American Patent. 

Zeit. agwd. Chem. — Zeitschrift fiir angewandte Ghemie. 
Zeit. physiol. Chem. — Hoppe-Seyler's Zeitschrift f iir physiologische Ghemie. 

* Descriptions of these German patents are given in Friedlander's 
" Fortschritte der Teerfarbenfabrikation," and abstracts of the more 
recent ones also in the Journal of the Ghemical Society (London) 
Abstracts, and in the Journal of the Society of Ghemical Industry. 



XI 



GLOSSARY 

OP CEETAIN CHEMICAL AND MEDICAL TEEMS 

Mbdical. 

Analgesic ==: diminishing pain. 

AfUipyretic = causing fall of body-temperature in fever. 

Hypnotic = sleep producing. 

Narcotic ^ producing marked diminution of mental activity tending to 
unconsciousness. 

Pressor ^ causing rise of arterial pressure, usually by constriction of the 
arterioles. 

Styptic « checking or arresting bleeding. 

Ghbmioal. 

Acyl is a term used to denote an acidic organic radicle derived from an 
organic acid by removal of the hydroxyl (OH) group from the groups, 
( — 00 — OH) or ( — SO2 — OH), containing the acidic hydrogen. 

E,g, Acetyl, OHs . GO—, from acetic acid, OH, . CO . OH. 

Benzoyl, O^Hg . CO — , from benzoic acid, 0^^ . CO . OH. 

Lactyl, CH3 . CH(OH) . CO—, from lactic acid, CHj . CH(OH) . CO . OH. 

yCO— /CO. OH 

Phthalyl, CgH.^ , from phthalic acid, CeH4<^ 

\C0— \CO.OH 

Benzene-sulphonyl, CgHo . SOg— , from benzene-sulphonic acid, 

C^5 . SOa . OH. 

Alkamine esters have the general formula R — CO — O — [CRiRJoj — ^NRjB4 ; 
they are formed by the esterification of an a.cid with an alcohol con- 
taining an amino-group. 

Alkyl is a term used to denote an organic radicle derived from a simple 
aliphatic hydrocarbon by removal of one hydrogen atom. 

E.g. Methyl, CH3, from methane, CH4 ; ethyl, GgHj, from ethane, CgHg. 

Aryl is a term used to denote an organic radicle derived from an aromatic 
hydrocarbon, by the removal of a hydrogen atom from the aromatic 
nucleus. 

E.g. Phenyl, C^Hg — , from benzene, CgH^; tolyl, CH3.CJH4 — , from 
toluene, CH3 . CgHg. Groups such as benzyl, CgHg . CH, — , obtained 
by removal of a hydrogen atom from the side-chain, must be re- 
garded as mixed alkyl and aryl groups. 



Xll 



CHAPTER I. 

INTRODUCTION— THE THEORY OF THE ACTION OP 

SYNTHETIC DRUGS. 

In bygone years Pharmacology was an empirical collection of 
recipes, hardly deserving the name of a science ; but a new era 
was begun with the investigation of medicinal substances by 
chemists in the early years of the nineteenth century. These re- 
searches soon bore fruit in the isolation of the active principles 
of many vegetable drugs, and it was found in many cases that 
the active compound was a nitrogenous substance of basic char- 
acter, and to this class of substance the name alkaloid was given. 

Although all vegetable drugs do not contain alkaloids, never- 
theless in the majority of cases definite chemical compounds, 
to the presence of which the action of the drug is due, have 
been isolated. These non-alkaloidal active principles include a 
large number of different types of chemical compound, but the 
class of substances known as glucosides (substances readily 
hydrolyzed by dilute acids or by enzymes into a sugar and 
another constituent which is generally physiologically active) is 
especially well represented. 

The isolation of the pure active compounds was of very 
great importance, as it opened up the possibility of an accurate 
study of the effect of dosage, and, as time went on, enabled 
quantitative measurements of the physiological effect of the 
drug to be made. Such progress was obviously impossible as 
long as investigators were compelled to deal with a crude drug 
of unknown strength and composition. By this means, also, 
secondary by-effects, often unpleasant and harmful, could be 
got rid of in those cases where they were due to the presence 
of substances other than the desired active principle. 

The study of the constitution of the active principles led 
to attempts at their synthetic production. For a long time, 
however, synthetic chemistry was not far enough advanced to 
succeed in the synthesis of such complex substances, and 
efforts were therefore made to find which portion of the mole- 
cule gave rise to the physiological effect in order that simpler 

I 



SYNTHETIC DRUGS 



analogous compounds might be prepared possessing the charac- 
teristic action of the drug. 

In this way it was found that the physiological action of the 
drug was in general dependent on its chemical nature, although 
naturally modified by differences in physical properties, such as 
solubility, volatility, etc. For instance, certain types of com- 
pounds often possess a characteristic action, e,g. the quaternary 
ammonium compounds have a paralytic action on the motor 
nerves. On the other hand, in the majority of cases the relation 
between chemical constitution and physiological action is ex- 
tremely obscure, and is usually to be found only within very 
narrow limits, outside which any generalizations that may have 
been made are apt to break down. Thus a very small change 
in the chemical constitution of a compound is often accom- 
panied by a complete change in its physiological action, as in 
the case of cocaine, a-cocaine, and a-eucaine, 

OH CHo 



CH3 

I 
OH2 



/ 



\ 



N— CH 



3 



\ 



\ 

( 



C— 0— CO— CjHj 



CH- 



/ H 
•CH— COOCH, 



Cooaine. 
CH- 



CH, 



/ 
CHg 

I N-CH3 

CH, 



O— CO— CgHg 



"S 



\ 



CH- 



\ 
C 

/ COOCH 
•CH, 



3 



a-Gocaine. 



CH 



CH 



% — ^ 



3 



•CH, 



0-C0-C,H5 



CHj- C- 



\ 
N— CH, C 

/ COOCH, 
CH, 



CH, 



a-Eucaine. 



INTRODUCTION 3 

the first of which has a strong local ansBsthetic action, whilst 
the second has no local anaesthetic action whatever, and the 
third — whiqh resembles a-cocaine in its chemical constitution 
more than it does cocaine — ^has a marked local anaesthetic 
action, just like cocaine itself. In this connection mention 
should be made of the fact that a very considerable difference 
in physiological action is often shown by stereo-isomerides, as 
in the case of d- and Z-nicotine, d- and Z-hyoscyamine, pilocar- 
pine, and isopilocarpine, etc. 

At this point it may be advisable to indicate the relation 
between the chemical composition and the physical proper- 
ties of a substance. It is held by some pharmacologists that 
the physiological action of a drug is conditioned solely by its 
physical properties, but even if this were always the case, it 
would not exclude a connection between the physiological 
action and the chemical constitution. It may be that the 
effect of some drugs is due to a subtle combination of various 
physical properties ; these cannot, however, be readily ascer- 
tained in the majority of cases, but we can endeavour to 
correlate the chemical constitution — which is the foundation 
of these properties — with the physiological action. Another 
point on which misconception seems to have arisen, is the 
question of whether a difference in properties between two 
substances is to be attributed to chemical or purely physical 
causes. The following quotation from a leading text-book of 
pharmacology will serve to illustrate this : " Yellow phosphorus, 
given by the mouth, is a violent poison, but red phosphorus, 
which only differs from it in its physical properties, is com- 
paratively innocuous. Yet were the two differently constituted 
chemically, the difference in their action would, no doubt, be 
referred to this fact." Now, according to all modern views, 
there is a considerable difference in the chemical constitution 
of the molecules of the two different kinds of phosphorus, a 
difference which is manifested in the great difference of their 
reactivity and of their toxic action. There is probably as great 
a chemical difference between yellow and red phosphorus as 
between acetylene, (CH)2, and benzene, (OH)g, but at present 
we have no means of accurately investigating the molecular 
complexity of the two solid varieties of phosphorus. 

I* 



4 SYNTHETIC DRUGS 

Although the action of some drags may be conditioned 
chiefly by their physical properties, yet there are others in 
which it is undoubtedly due to their chemical character {e,g, 
organic arsenic derivatives certainly owe their trypanocidal and 
anti-syphilitic action to the presence of the arsenic). The 
term chemical " character " rather than ** constitution " is used 
deliberately, as in many cases the physiological action of a 
substance may be traced to some specific chemical property, 
which is not necessarily closely connected with its constitution. 
For example, the poisonous character of oxalic acid and its 
soluble "salts could hardly be deduced from its structural 
formula, but its toxicity is sufficiently explained by the fact 
that it forms an insoluble calcium salt, a sufficient quantity 
of calcium in solution being essential for the welfare of the 
organism.^ The higher members of this series of dibasic acids, 
having more soluble calcium salts, are proportionately less 
toxic. In other cases, however, some kind of relation has been 
traced between the presence of certain groupings in the mole- 
cule and the appearance of certain more or less characteristic 
physiological effects. These relations may be used in attempt- 
ing to prepare new synthetic drugs, but it is impossible to 
forecast the action of any new substance with certainty, and 
careful pharmacological experiments must be made before a 
new compound can be introduced as a drug. 

Many interesting facts concerning the relation between 
chemical constitution and physiological action are described by 
Pyman in a lecture to the Chemical Society.^ 

Guidance in our efforts to obtain synthetic drugs may also 
be obtained from a study of the changes undergone by com- 
pounds in the organism. These changes are usually in the 
direction of the transformation of an active and poisonous 
substance into a less active and less harmful one. Thus, in 
order to replace a drug by a new product in which harmful 
by-effects are eliminated, we can often attain the desired object 
by studying the changes undergone by the former in the 

^ This aocounts for the tozioity of the salts and dilute solutions of the 
acid; strong solutions of the acid are poisonous Iq t^e same way as other 
acids ; i.6. on account of their corrosive ftctiont 

3 /. C. S., Ill (1917), 1103. 



iNfkODVCTION 5 

6rganism, and by taking for the atarting-point of the new 
drug the product of the metabolism of the original drug. For 
example, it was found that aniline is oxidized by the body 
into para amino-phenol, and this observation led to the intro- 
duction into medicine of a large number of derivatives of para 
amino-phenol, of which phenacetin is the best-known example. 
The theories that have been advanced to explain the action 
of various drugs are chiefly concerned with carbon compounds, 
as the latter offer practically the only means of comparing sub- 
stances possessing definite structural relationships with one 
another. The influence of the chemical constitution pf a sub- 
stance on its physiological effect can be seen from the fact that 
definite changes in the chemical constitution of substances 
belonging to the same class, are usually accompanied by definite 
changes in the physiological effect, and further that the addition 
of certain molecular groups to differently acting substances can 
change them into similarly acting or equally inactive bodies. 
As an instance of this point, mention may be made of the dis- 
covery of Crum Brown and Fraser,^ that various alkaloids pos- 
sessing the most diverse physiological actions, on combination 
with alkyl halides to form quaternary ammonium derivatives — 

NR1R2R3 + RX =. ^NRiRgRs, where . RiRgRj are organic 

radicles of any complexity, and EX stands for an alkyl halide 
snch as methyl iodide, CH3I, ethyl bromide, CgHgBr, etc. — yield 
substances which in almost every case possess the property of 
paralysing the motor-nerve endings in the same manner as 
curare. In this way, by the process of methylation, one can 
obtain from all tertiary bases (NB1E2B3), quaternary ammonium 

compounds, ^NRiR2R3, which are very, and often dispropor- 
tionately, poisonous compared with the original bases. Curare 
itself contains a tertiary base, curine, which is not very poison- 
ous, as well as the far more poisonous ammonium base, curarine. 
The former on methylation yields the latter, which is 226 times 
as poisonous as the original substance. 

^Crum Brown and Fraser, Trans. Boy, Soc. Ed., 26 (1869), 707; Crum 
Brown and Fraser, Proc. Boy, Soc, Ed,, 6 (1869), 560. 



6 SYNTHETIC DRUGS 

^ On the other hand, the following examples may be quoted 
to show that the addition of particular groups to certain sub- 
stances may weaken or destroy their action. This is well 
illustrated by the effect of the entrance of acidic groups into 
the molecule, thus substances containing a hydroxyl group, 
on combination with sulphuric acid, lose their toxic properties. 
For instance, phenol is very poisonous, but phenol-sulphuric 
acid, in the form of its sodium salt, CgH^ — — SOg — ONa, 
is harmless. Morphine, Ci7Hi7NO(OH)2, is an extremely 
powerful and poisonous drug, but morphine-sulphuric acid, 
Ci7Hi7NO(OH) . O . SO2 . OH, is practically inert, and can be 
given in doses of 5 grams without any harm. This fact should 
be borne in mind in considering the attempts that are often 
made of introducing the sulphonic acids of various drugs into 
medicine, as in nearly every case these are bound to be useless. 
The effect of introducing the carboxylic acid group (CO — OH) 
is often the same as that of introducing the sulphonic acid 
group ( — SOg — OH). For example, the toxic substance methyl- 
amine, NHg — CH3, is thus changed into the harmless glycine, 
NHg — CHg — COOH. The mere addition of acid radicles, such 
as acetyl, — GO — CHg, without actually converting the sub- 
stance into an acid may often be sufficient ; thus acetamide, 
NHg — CO — CH3, is practically harmless, but ammonia, NH3, 
is poisonous ; acetanilide, CgHg . NH . CO . CHg, is less poison- 
ous than aniline, C^Hg . NHg. 

An example of an opposite kind is furnished by the effect of 
the addition of hydrogen to cyclic basis, which is almost invari- 
ably to increase their activity, and also their toxic properties. 
Other examples of this kind will be adduced later, but sufficient 
have been mentioned to indicate that similar alterations of 
differently acting compounds often produce similar or identical 
alterations in the physiological effect. 

Bhrlich considers that the selective action of a compound 
for certain cells depends on the coming together of particular 
groups in the molecule in some sort of chemical connection 
with the cell substance. It is only when the compound is held 
to the tissues (" anchored ") by these groups, that the whole 
complex molecule can take effect and exert its characteristic 
physiological action. If, therefore, the character of these 



INTRODUCTION y 

special " anchoring *' groups be altered, the substance can no 
longer exert its action on these particular cells, but it may 
happen that the alteration of the " anchoring " group* causes 
the substance to become '' anchored *' to a different set of cells, 
and so to produce a different physiological effect. Examples 
of this type will be quoted subsequently. 

These views may be more readily understood by analogy 
with Witt's theory of dyeing, according to which the colour of 
a substance is due to the presence of certain '* chromophore " 
groups, such as the azo group, — N = N — , while, for the coloured 
substance to have dyeing properties, it is necessary for another, 
salt-forming, group to be present, by which it can be held fast 
to the fibre. A dye, therefore, must contain both a chromo- 
phore group and a salt-forming group, and in the same way, 
a drug is* supposed, besides containing an active group, the 
" pharmacophore," corresponding to the chromophore, to con- 
tain also an anchoring group, corresponding to the salt-forming 
group. 

This analogy may be extended, and the phenomena observed 
in staining nerve tissues may be compared with the biochemical 
processes which take place between poisons and the living 
tissue. 

According to Ehrlich, the process of dyeing i$ similar to 
that which takes place when a poison is injected into the body. 
Thus, if a wool fibre be immersed in a dilute solution of picric 
acid, the colour is withdrawn from the solution and enters the 
fibre. The fibres of an animal tissue are regarded, in the same 
way, as withdrawing the dyestuff from the solution, and fixing 
it, if it is more soluble in them than in the original solution. 
If the dyestuff is more soluble in another solvent, e,g. alcohol, 
than in 'the tissue, then the latter can be again decolorized by 
shaking it in alcohol. 

Now, all dyes capable of dyeing nerve cells lose this pro- 
perty if a sulphonic acid group is introduced into the molecule. 
The bulk of nerve-dyes can be extracted from their aqueous 
solutions with ether, but the sulphonic acids cannot owing to 
their greater solubility in water. It is therefore supposed that 
there are certain substances in the nerve tissues which act like 
ether does in the test-tube, so that the strong action of certain 



6 SYNTHETIC DRUGS 

poisons on the brain and nervous tissues is due to their being 
extracted in the same way as they can be extracted with ether. 

Ehrlich's views have proved to be very stimulating and 
fruitful, especially in recent years, and some examples of their 
application are given later in this chapter. Further reference 
to them will be found in the sections dealing with Antiseptics 
and Organic Arsenic Compounds (pp. 170-173). A full account 
would, however, be beyond the scope of this book, and for that 
the reader is advised to refer to Ehrlich's own writings.^ 

A theory of the action of poisons, in which the subject is 
regarded from a different point of view, is that due to Loew.^ 
It states that all substances which are capable of acting on 
aldehyde or amino groups, even when in dilute solution, must 
be poisons for living tissue, on which they will exert a sub- 
stituting action. The greater the reactivity of a substance for 
aldehyde (CHO) or amino (NHj) groups, the greater will be 
its physiological effect and its toxicity. For example, phenyl- 
hydrazine, CgHfi . NH . NHj, and hydroxylamine, NHg . OH, 
which are so reactive to ketone and aldehyde groups, are strong 
poisons, both to plants and animals. Aniline, CgHg . Nn2, 
which reacts less readily with aldehydes than does phenyl- 
hydrazine, is less poisonous; and similarly ammonia, NHg, 
is less poisonous than hydrazine, HgN — NHg. Substances 
containing tertiary combined nitrogen are usually less toxic 
than the corresponding substance where the nitrogen is present 
in the more reactive form of a secondary imino (NH) group. 
This is exemplified by the fact that if the hydrogen of the 
NH group in many alkaloids lis replaced by a methyl group, 
the resulting tertiary base is far less poisonous than the 
original alkaloid. In the same way, if one of the hydrogen 
atoms of the NHj group in aniline is replaced by an alkyl 
group, the toxicity is diminished, as the substance reacts less 
readily with aldehydes. A similar explanation is offered of the 
fact that piperidine is far more toxic than pyridine, and tetra- 
hydroquinoline far more toxic than quinoline, namely, that the 

^Deut, med. W, (1898), p. 1062; Proc. Roy. Soc., 66 (1900), 424; Zeit. 
physiol Chem., 47 (1906), 173; *• Studies on Immunity," J. Wiley & Sons 
(1906), 404-42. 

' ** Naturliches System der Giftwirkung." Miitiich, 1893. 



INTRODUCTION 9 

reduced compounds, which contain secondary nitrogen in the 
place of tertiary, have a greater reactivity with protoplasm. 
This view is supported by the fact that the toxicity of substances 
with labile amino groups is increased by the addition of a second 
amino group, but is lessened when an amino group is changed 
into an imino, NH, group. Thus, para-phenylene-diamine, 

NHg \ y >NH«^, is more toxic than aniline. In general, if the 

chemical character of a poison is made more labile by any 

change in the character of the molecule, then it becomes more 

toxic, and vice versd. An example of this is shown by the 

hydroxybenzenes, in which the increased reactivity due to 

the entrance of hydroxyl groups into the benzene ring is 

accompanied by an increase in the toxicity of the substance. 

OH 
/\0H 



^ IS more poisonous 
than catechol, [ 1 ^^ which contains only two hydroxyl 



Thus, trihydroxy-benzene, pyrogallol, 

r^OH 

'OH' 

groups, and this in turn is more poisonous than phenol (mono- 

/NOH 
hydroxybenzene), . The labile substance, ammonium 

Bulphocyanide, is toxic to plants, but the more stable isomer, 

thio-urea, is not. Substances with carbon atoms united by 

" double bonds " are generally more reactive and more toxic 

than closely related compounds with simple linkage. Neurine 

is more poisonous than choline, and other instances of this 

kind are mentioned in the next chapter. The toxicity of 

phenols is attributed to their reactivity, especially with 

aldehydes. This reactivity is diminished by the entrance of 

acid groups, such as the carboxyl, OOOH, and the sulphonic 

acid group, SOg — OH, and this diminution in the reactivity 

is accompanied by a diminution of their toxic power. For 

/NCOOH 
example, salicylic acid, , is less poisonous than 

\yOH 

phenol, I . In the same way, saccharin, 

• CO 
CeH/^^NH 
SOa 



lo SYNTHETIC DRUGS 

is not at all poisonous, as the presence of the oarboxyl and 
the sulphonic acid groups so much diminishes the reactivity 
of the imino group. 

These views of Loew, which are both simple and very sug- 
gestive, can nevertheless only be applied to certain groups 
of substances which react with aldehyde and amino groups. 
They offer no explanation of the selective action of different 
tissues for various drugs, as they are applied simply to proto- 
plasm, and the protoplasm of any and every tissue has labile 
aldehyde and amino groups, which, according to this view, 
should' react with the drug. Nevertheless, the theory is of 
value in co-ordinating the action of the various members of 
certain classes of compounds. 

A physical theory of the action of various hypnotics will be 
discussed in the chapter dealing with the hypnotics. 

To return to Ehrlich's theory of " anchoring ** groups, many 
examples may be given to illustrate the application of the 
theory. In general it is supposed that there are two kinds of 
groups in the molecule of an active substance, necessary for the 
action to appear, but in some cases the active group and the 
anchoring group may be one and the same. If the anchoring 
group is altered or removed, then a different physiological effect 
from the original may become apparent if there is present a 
second possible anchoring group, which can now manifest itself 
more strongly. As these other anchoring groups may effect 
different tissues from those affected by the original anchoring 
groups, so a different physiological effect may be produced, or 
one of the special physiological effects of the substance may 
become enhanced. In the first place, the most chemically re- 
active anchoring group dominates the situation. 

For example, morphine has a strong hypnotic effect, and 
the anchoring group is probably one of the hydroxyl groups. 
If these are combined with sulphuric acid, then the mor- 
phine cannot become " anchored " to the nerve tissues ^ of the 

^ It should be pointed out that the loss of the physiological activity of 
morphine on sulphonation can be accounted for, from the physical point of 
view, by reason of the change of its solubility. The more soluble substance 
cannot become ** anchored'* to the tissues. These two points of view are 
not, however, antagonistic, and are merely different methods of viewing 
the same experimental facts. 



INTRODUCTION tt 

central nervous system, and the resulting substance has no 
effect at all. If the hydroxyl is only altered by the entrance 
of an organic radicle, with the formation of substances such as 
methyl, ethyl, or acetyl derivatives, then the hypnotic effect is 
thrust into the background, while the action on the respiratory 
centres, produced by morphine to a slight extent, becomes 
much enhanced and dominates the physiological effect (codeine, 
heroin, etc.). 

In those cases where the presence of an acid group prevents 
the substance from acting on certain tissues in spite of the 
presence of an anchoring group, the esterification of the acid 
group causes the physiological action to appear. To illustrate 
this, the esterifying group must of itself play no part in the 
physiological effect, which must reside solely in the original 
substance, and only be hindered from appearing by the presence 
of the acid group. 

For example, arecaidine has no action at all on animals, but 
arecoline, its methyl ester, is poisonous, and has physiological 

CH CH 

HoC/'^C— COOH HoC/'^C— COOCH, 



H«C 



2' 



CHo SoG 



3 



CHc 



N— CH3 N— CHg 

Arecaidine. ArecoUae. 

effects similar to those of pilocarpine and muscarine. The ethyl 
ester acts similarly to the methyl ester. 

A precisely similar example is furnished by cocaine, which 
is the methyl ester of benzoyl-ecgonine. Benzoyl-ecgonine 
itself is far less active, and is twenty times less toxic than 
cocaine, owing to the presence of the carboxyl group. It is 
only when this group is esterified, that the typical action of 
cocaine appears, and it is immaterial by which alcohol the ester 
formation is accomplished. In every case the typical action 
of cocaine appears when the carboxyl group is masked, and 
therefore it is not the alkyl group which is active, but its 
presence simply serves to destroy the effect of the group which 
is inhibiting the characteristic action of the drug. When this 
group is masked, then the typical ** anchoring " group can take 



ta SYNTHETIC bRUO$ 

effect. Thus it mB,y possibly be that for cocaine to act as a locat 

\ 
ansBstheiic, it must be anchored to the tissues by the N — GH^ 

/ 

group; or at any rate by some portion of the molecule other than 

the carboxyl group, but that if a free carboxyl group be present, 

it becomes anchored by this instead, and so fails to produce 

its characteristic action. 

One can thus alter inactive compounds into active ones, or 
vice versd, or can alter the nature of the action of some com- 
pounds by means of a chemical change which alters the 
group. In this way, if the most prominent property of a drug 
becomes suspended or diminished, a comparatively masked 
property becomes developed. 

Closely connected with the relation between the constitution 
and the physiological action of a drug is the second question, of 
whether there is any connection between the action and the 
chemical changes which the substance undergoes in the organ- 
ism. Robert considers that the strength of the action of a drug 
is in no way proportional to the amount of the chemical change 
which it undergoes in the organism. For instance, very active 
substances, like atropine and strychnine, pass through the body 
practically unchanged, but an inactive body like tyrosine is 
completely oxidized by the organism into carbon dioxide and 
water. Conversely in the case of many compounds, it can be 
seen that when they have an effect on the body, they have 
undergone a chemical change. This is also the case with 
many physiologically active organic compounds, which often 
show a chemical alteration in the organism. It would therefore 
seem as if there were no relatioa between the ch^anges under- 
gone by a drug and its physiological action, but nevertheless 
some facts can be cited against the view that there is absolutely 
no connection to be traced. 

It has baen pointed out, in discussing the relation between 
chemical constitution and physiological action, that tpide gen- 
eralizations cannot be drawn, and that it is only in the case 
of closely related compounds that relationships can be traced. 
In the same way, wibh regard to the relation between chemical 
change and physiological action, a connection can be found 



INTRODUCTION 



13 



in certain cases of closely related compoands. In many oases 
physiologically active compounds show a degradation of the 
molecule, and these same substances, if they are made so 
resistant that they no longer suffer any alteration in the 
organism, then become inactive. For example, xanthine has no 
tonic action on the heart muscle, but theobromine (dimethyl- 
xantbine) has a slight tonic action, and caffeine (tri-methyl- 
xantnine) has a still more marked tonic action, from which it 
will be seen that the addition of methyl groups to the nitrogen 
of xanthine adds a special action on the heart to the ordinary 
physiological action of xanthine. Experiments, made to ascer- 
tain the fate of these compounds in the organism, show that the 
products of metabolism found in the urine after the administra- 
tion of caffeine and theobromine contain xanthine bases, poorer 
in methyl groups than the substances originally administered. 

HN CO HN CO 




H 



C— N 



/ 



\ 



CH 



HN 



C— N 



^ 



CH3— N 




CH, 



C— N 



/ 



Xanthine. 



C— N 

Theobromine. 



\ 

CH 



CH,— N 



CH,— N 



^8 




CH 



— N 



/ 



3 



\ 



CH 



•N 



^ 



Caffeine. 



This indicates that the methyl groups have been split off in the 
organism. In experiments on dogs, caffeine gives first theophyl- 
line and then 3-mono-methyl-xanthine, smaller quantities of the 
two other di-methyl compounds, theobromine and para-xanthine, 
being also formed.^ In man it is degraded into theophylline. 

^ Kruger and Bchmid, 2ieit. physiol. Chem.^ 36 (1902), 1, 



14 



SYNTHETIC DRUGS 



CH,— N 



CH,— N 




HN 



CH 



C— N 
Theophylline. 

CH,— N- 



CH,— N 




H 



C— N 



/ 



\ 



CH 



C— N 



/ 



3 moQo-methyl-xanthine. 



CO 



00 



CH 



C— N 



/ 



3 



HN- 



•C— N 



\ 
.CH 



Para-xanthine. 

In both cases, therefore, we have a splitting off of some of the 
methyl groups, the groups which appear to be responsible for 
the tonic action on the heart. This case indicates that there 
is sometimes a relationship between the physiological action 
and the changes undergone by the substance in the organism. 
Another well-known instance is afforded by the sulphone de- 
rivatives, the hypnotic action of which has been shown to be 
connected with the presence of ethyl groups in the molecule. 
The methyl derivatives are inert, and pass through the organism 
unchanged ; the ethyl derivatives produce sleep, and are almost 
completely decomposed by the organism. 

In the case of the alkaloids, it is very difficult in most cases 
to obtain any knowledge of the mechanism of their action, and 
generally they seem to pass out of the organism for the most 
part unchanged. Hence it has been assumed that the action 
of some of these is " catalytic," an assumption that explains 
nothing. Another view is that the small portion of the alka- 
loid that cannot be recovered from the body has undergone a 
chemical change to which its action is due. 

Compared with food-stuffs, most drugs are destroyed by the 
organism with difficulty, and they owe their activity to this 



INTRODUCTION 15 

property, but if they are absolutely resistant they are quite 
inactive. Those substances which have a specific action must 
be fairly resistant, otherwise they would react with all proto- 
plasm. In the synthesis of drugs we make use of this property 
by conferring an artificial resistance on the synthetic substance, 
so as to prevent it from reacting too suddenly, and also to 
prevent it from reacting with all tissues, so that it does not 
show undesirable by-effects. For this reason, all substances 
which can react with every kind of tissue cannot be used as 
drugs, unless the reactivity is artificially diminished, or the 
dose made very small, in which case they can be made useful 
{e,g. formaldehyde, hydrocyanic acid). 

In some substances the physiological effect seems to be due 
more to the stereo-chemical configuration than to the chemical 
constitution. One general instance will be a sufficient support 
for this statement. It has already been pointed out that all 
ammonium bases have a paralytic action on the motor nerves, 
and that this action is quite independent of the structure of 
the rest of the molecule. Even the presence of nitrogen is not 
necessary, as a similar effect is shown in those bases where 
the nitrogen is replaced by phosphorus, arsenic, or antimony, 
and it therefore seems that the effect is due to the configur- 
ation of the ammonium, phosphonium, or arsonium group, 
this being a three-dimensional (space) one, while that of the 
original amines almost certainly lies in one plane. This view 
is strongly supported by the fact that dimethyl sulphide, 
(CHj,)2S, and diethyl sulphide, where the sulphur is divalent, 
and where the configuration must lie in one plane, are 
practically inert, but that tri-methyl sulphonium hydroxide, 
(CH3)3SOH, and trimethyl sulphonium iodide resemble the 
ammonium bases in having a curare-like action on the motor 
nerves. In these compounds, where the sulphur is tetravalent, 
its valencies are distributed in three dimensions, as shown by 
the fact that optically active sulphur compounds of this type 
have been prepared.^ 

* SmUes, /. C. -S., 77 (1900), 1174 ; Pope and Peaohey, J. C, S., 77 (1900), 



CHAPTER II. 

THE EFFECT OF VARIOUS ELEMENTS AND RADICLES. 

Inorganic Elements. — In 1839 Blake ^ noticed that the 
action of salts, injected into the blood, depended only on the 
electro-positive half, and hardly at all on the electro-negative. 
This is analogous to the action of most esters, which generally 
resembles that of the alcohol from which they are derived, the 
explanation in both cases being that acids are usually physio- 
logically inert. Later on ' it was shown that in any given group 
of isomorphous substances the action is similar, and is usually 
increased with increase in atomic weight. This was shown to 
be the case with Li, Na, Rb, Cs, Ag, Tl ; and with Mg, Mn, Co, 
Ni, Cu, Zn, Gd, and with Ca, Sr, Ba. The only exceptions 
found were in the case of potassium and ammonium, which 
differ from the other isomorphous substances of the group. 
But these salts are also exceptions to Mitscherlich*s law that 
isomorphous substances have similar spectra. It was therefore 
supposed that physiological action depends on intramolecular 
vibrations in the same way as the spectra depend on these. 
The statement made above that isomorphous elements have 
a similar physiological effect, which becomes stronger with 
increase in atomic weight, only holds good in the case of electro- 
positive elements ; in the case of negative elements, such as the 
halogens, there is no relation between physiological effect and 
atomic weight. Elements forming two series of salts show 
different effects, according to which class the salt belongs, ferric 
salts, for instance, differing considerably from ferrous. In 
many salts the action appears to be due to the ions into which the 
salt dissociates ; for example, potassium ferrocyanide is excreted 
for the most part unchanged, and has neither the action of a 

• C. R,, 8 (1839), 875 ; Proc. Roy, Soc., 4 (1841), 166, 284, 286. 
'B«r., 14(1881), 391. 

l6 



THE EFFECT OF VARIOUS ELEMENTS AND RADICLES 17 

ferrous salt nor of a cyanide, and similarly sodium plantino- 
cyanide, which is found unchanged in the urine, is almost free 
from poisonous effects, thus differing hoth from the cyanides 
and the platinum salts. 

The effect of ionization is strikingly indicated hy the mercury 
salts. Mercuric chloride, HgClj, is ionized and extremely 
poisonous, hut the cyanide, Eg(CN)2, though soluble, is almost 
non-ionized and is far less poisonous. The insoluble and 
practically non-ionized mercurous chloride (calomel), HgCl, 
is comparatively non-poisonous. 

Phosphonium, arsonium, and stibonium bases do not show 
the action of the other phosphorus, arsenic, and antimony 
compounds. On the contrary, these compounds resemble the 
substituted ammonium bases, such as those present in curare, 
in haying a paralytic action on the motor nerves. In these 
cases we do not get the characteristic action of the poisonous 
elements themselves, but rather one resembling the analogous 
compounds of tl^e indifferent element nitrogen. 

Badigles and Elements in Obqanic Compounds. 

Action of Hydrocarbons and Effect of Alkyl Groups. — 

According to Schmiedeberg ^ the action of aliphatic compounds 
is governed by the following rules : — 

The physiological activity of substances (especially aliphatic) 
depends chiefly on physical properties. The readiness with 
which a substance is absorbed is a very important point, as 
obviously a substance that is not absorbed can have no action 
on the system. Volatility and solubility in water are of great 
importance, a fact which is illustrated by the paraffin series, 
the lower and more volatile members of which show the 
characteristic narcotic effect of the hydrocarbon groups, while 
the insoluble non-volatile higher paraffins are without any 
action at all. 

The following rules show the effect of substituent alkyl 
groups : — 

(1) Very poisonous radicles, on, substitution by simple alkyl 
groups, lose the intensity of the original character of the group. 

M. a. P. P.. 20 (1886), 201. 
2 



i8 SYNTHETIC DRUGS 

For example, by substituting alkyl radicles for the hydrogen of 
HON, the nitriles, ECN, and isonitriles, R — N = C, are obtained, 
and only become poisonous when HON is split off in the or- 
ganism. Also cacodyl oxide, (CH3)2As— 0— As(CH3)2, where 
the oxygen of arsenious oxide is replaced by two methyl groups, 
does not show the characteristic arsenic effect until after it has 
begun to decompose in the body. 

(2) On the other hand, the effect of the alkyl groups can 
be lessened or altogether lost by combination with other atoms 
or groups. For instance, the amines of the fatty series (e,g. 
mono-, di-, and tri-methylamines) behave like ammonia and 
have no narcotic action. Nevertheless, the first rule holds 
in this case as well, as these amines are less toxic than 
ammonia. 

(3) When a compound is formed by the union of two groups 
through an oxygen atom, then the physiological effect depends 
upon the nature of the two components, each of which acts 
independently of the other. In tl^osQ cases where, both parts 
of the compound are similar or equivalent alkyl groups, as in 
the case of the simple and niixed ethers, then the action of 
the whole compound is a simple one, and these substances rer 
semble the corresponding alcohols in their physiological effect. 
To this class of substances should be added those esters the 
acids of which yield neutral (sodium) salts without any specific 
physiological action. For this reason, acetic ester and its 
homologues are classed with the alcohols. If, on the contrary, 
the acid has a specific action of its own, then this becomes 
apparent in the ester, and exerts a modifying influence on the 
physiological effect of the alkyl group — e.g. amiyl nitrite. 

These rules of Schmiedeberg are of value, not only in 
summarizing the effect of alkyl groups, but, as can be seen 
above, are also useful as applied to other groups of substances, 
especially the ethers and the alcohols, the effect of which is due 
to the alkyl groups contained in them. 

The hydrocarbons of the methane series are, as would be 
expected from their chemical nature, less active physiologically 
than those of the ethylene, acetylene, or benzene series. The 
lower members, when inhaled, produce ansBsthesia and sleep, 
and in larger quantities asj^hyxiation. The toxicity and the 



THE EFFECT OF VARIOUS ELEMENTS AND RADICLES 19 

strength of the narcotic action increase as the series is ascended, 
but on further ascending the series, the action diminishes owing 
to their diminished volatility and solubility, so that the higher 
members are quite inert. The members of the ethylene aeries 
have a similar narcotic action ; amylene, CgHjQ, resembles 
chloroform in its narcotic properties. 

The benzene hydrocarbons have a paralysing action on the 
motor nerves, and a more noteworthy action on the brain and 
cord, causing lethargy and somnolence. Bromobenzene and 
chlorobenzene act in the same way as benzene itself. Naphtha- 
lene, C^oHg, is less toxic than benzene, but slows the respiration 
and, in fever, lowers the temperature. It also has the property 
of decreasing nitrogen metabolism. Diphenyl is physiologically 
inert, while thiophene, furfurane and pyrrol resemble benzene 
to a certain extent. 

Effect of Alkyl Groups. — Some of the effects of introducing 
alkyl groups into a compound have already been mentioned 
in connection with Schmiedeberg's rules, but there are many 
different effects to which attention may be given. The con- 
vulsive properties of ammonia are diminished by the entrance 
of methyl groups, trimethylamine being free from these effects. 
In aniline, replacement of the hydrogen of the amino group 
causes diminution of the convulsive properties as with ammonia, 
but replacement of the hydrogen of the nucleus by methyl 
groups causes an increase in these effects. The marked in- 
fluence of the entrance of methyl groups into the xanthine 
molecule has already been pointed out. The foregoing ex- 
amples show that the addition of a methyl group to a nitrogen 
atom can produce fery diverse effects, and a similar variety can 
be found in the effect of the methylation of an hydroxyl group. 
The a!kyl ethers of the type B . O . B, where B represents 
an aliphatic hydrocarbon radicle, are distinguished by their 
resistance towards oxidation, and physiologically they show a 
marked hypnotic action, as in the case of ordinary ethyl ether, 
G2H5 — O— G2H5. This hypnotic action is also shoWn by many 
other compounds containing an ethoxy group, — — C^Hg, such 
as ethoxy-caffeine. 

In many cases, replacement of the hydrogen of an hydroxyl 
group by a methyl group diminishes the physiological activity. 

2 * 



20 SYNTHETIC DRUGS 

OH 

For instance, catechol, ^ X ^H, is more poisonous than 

OH 
guaiacol, < ( ^ OCHg, and this in turn is more poisonous 

0CH3 

than veratrole, ^ ^ CH^, and ortho-methoxy-benzoic acid, 

OCH3 
< >COOH, and anisic acid, CH^O< >COOH, are less 

OH 

active than salicylic acid, ^ ^ COOH. On the other hand, 
in some cases the activity of a compound is increased by the 
methylation of an hydroxyl group. For instance, di-methyl- 
resorcinol is extremely poisonous, far more so than resorcinol — 

OCHs OH 




an 



In some cases, the methylation of a hydroxyl, and even 
more often of a carboxyl group, may cause a very marked 
change in the physiological action of a compound, owing to the 
methylation producing a new anchoring group for the molecule. 
It has already been pointed out how the entrance of an alkyl 
group into certain acids often causes the full appearance of 
certain previously masked properties, as in the case of cocaine, 
arecoline, etc. Possibly a similar explanation may be given 
of the antipyretic action of phenyl-dimethyl-pyrazolone (anti- 
pyrine), phenyl-methyl-pyrazolone being inert. 

CHj— C— OH CH3.— C=CH 



CH3. 



■N CO H— N COjJ 

N-CeH, N-CeH, 



Phenyl-dimethyl-pyrazolone Phenyl-methyl-pyrazolone. 

(antipyrine). 

In the chapter on hypnotics, reference is made to the 
importance of ethyl groups in the hypnotic ketones and sul- 
phones, in which compounds the ethyl groups seem to have a 
marked influence in causing the hypnotic character to appear, 
whereas methyl groups are entirely without this influence. In 
fact, there appears to be a marked difference between the ethyl 



THE EFFECT OF VARIOUS ELEMENTS AND RADICLES 21 

and methyl groups with respect to their action on the central 
nervous system, for which the former seem to have a special 
afl&nity. Other groups of compounds show similar relation- 
ships. An interesting experimental result points to the same 
conclusion, as it has heen shown that certain dyes, containing 
the diethyl-amino group, N(02H5)2, possess the property of 
dyeing the nerve fibres, but the corresponding dyes containing 
the dimethyl-amino group, N(CHg)2, do not have this property 
(Ehrlich and Michaelis). 

Another example of the difference between methyl and 
ethyl groups is furnished by para - phenetol - carbamide, 
C2H5O . CfiH^ , NH . CO . NH2 (Dulcin), which is two hundred 
times sweeter than sugar, whilst the corresponding methyl 
derivative, CH3O , CgH^ — NH — CO — NHg, is tasteless. 

The entrance of a phenyl group often produces a marked 
change in the physiological action of a compound, but the effect 
varies greatly in different cases, and no general rule can be 
given. 

Effect of Hydroxyl Groups. — The entrance of an hydroxyl 

group into aliphatic compounds usually produces a weakening 

of their physiological activity, and this weakening effect is 

roughly proportional to the number of the hydroxyl groups. 

For example, the narcotic and poisonous alcohols give rise to 

the inactive glycols, glycerol, mannitol, etc., and from the 

very active aldehydes are obtained the less active aldols, such 

as 

/OH 
CH3— CHC 



CH2 . CHO, 

and by the entry of more hydroxyl groups, the totally inactive 
aldoses (glucose, etc., CH2 . OH(CH . OH)^ . CHO). A similar 
effect is often produced in many other compounds, for example, 
caffeine, the physiological effect being lost in hydroxy-caffeine. 
In the aromatic compounds, the entrance of a hydroxyl 
group usually causes an increase in both the physiological effect 
and the toxicity. The entrance of a hydroxyl group in benzene 
itself causes a great increase in the toxicity, together with the 
appearance of the strong antiseptic properties for which phenol 
is well known. In the case of a more inert aromatic substance 



22 SYNTHETIC DRUGS 

such as benzoic acid, the entrance of a hydroxyl group is again 
accompanied by an increase in physiological activity, ortho- 
hydroxy-benzoic acid (salicylic acid) having well*marked anti- 
septic properties as well as an apparently specific action in 
rheumatism. 

The large number of facts known as to the action of com- 
pounds containing a hydroxyl group do not lend themselves 
to the view that this group has an action of its own, but they 
point rather to the fact that it very often performs the function 
of an " anchoring *' group. The modification of such groups by 
esterification or alkylation neutralizes or alters the effect of these 
groups in '' anchoring " the substance to a particular tissue. If 
an acyl group enters the hydroxyl group (esterification), then 
various different effects may be produced. In those cases where 
the ester is hydrolyzed in the organism, its action is due to that 
of the original hydroxylic substance, together with that (if any) 
of the sodium salt of the acid. As the greater number of acids 
are inert, the action of most esters isMue to a delayed action of 
the alcohol from which they are demed. In some" cases, the 
esters do not appear to be hydrolyzed by thQ organism, and they 
then do not behave in the fashion indicated by the foregoing 
statement. For example, triacetyl glycerol (triacetin) — 

CHg— 0— CO— CH3 

CH— 0— CO— CH3 

CH2— 0— CO— CH3 

does not show the action of glycerol or of sodium acetate, both 
of which are practically inert, but possesses a specific action on 
the nervous system, and is poisonous. Glyceryl ether — 

CH^ — CH — CH2 

.'■ / 000 

.III 

CH2 — CH — CH2 

is also an hypnotic, this being an example of the fact that alkyl 
compounds of this kind, obtained by the addition of an alkyl 
residue to a hydroxyl group, often show hypnotic properties ; 



THE EFFECT OF VARIOUS ELEMENTS AND RADICLES 23 

for example, ethoxy- caffeine. In the case of the ethers, such 
as ordinary ethyl ether, the narcotic properties are strictly in 
accordance with the close resemblance between the chemical 
properties of the ethers and the parent hydrocarbons them- 
selves, the narcotic action being simply that of the alkyl 
groups, as stated by Schmiedeberg in the third of his rules 
{loc, ciL). 

Other conditions being equal, primary alcohols are less 
active than secondary, and these are in turn less active than 
tertiary. In homologous series, those members with long side 
chains are in general more active, a rule which also holds for 
benzene derivatives with side chains. The chief action of ethyl 
alcohol is on the nervous system, the narcotic effect being pre- 
ceded by a loss of control of the higher centres, an effect which 
has led to the mistaken belief that alcohol in small quantities 
acts as a " stimulant." Although the subject is somewhat con- 
troversial, the balance of the pharmacological evidence suggests 
that there is no justification for the medicinal use of alcohol. 
An excellent account of 'modern pharmacological opinion on 
this subject is given by Cushny in Science Progress, No. 8, 
April, 1908. It is there suggested that if alcohol had been 
introduced as a modern synthetic remedy, it would probably 
not have survived more than six months, owing to the fact 
that any of the desirable effects produced by alcohol can be 
produced by other drugs with greater certainty. The action of 
the higher alcohols resembles that of ethyl alcohol, but the 
intensity increases as the series is ascended. 

Effect of Halog^en in Org^anic Compounds. — The most im- 
portant effect of the entrance of chlorine into the molecule of 
aliphatic compounds is an increase in their narcotic action, 
but this useful property is accompanied by an increase in their 
depressant action on the heart and blood-vessels. Narcotic 
action and lowering of blood-pressure appear to be general 
properties of chlorine compounds, and an illustration of the 
fact that narcotic action, and also the toxicity of chlorine com- 
pounds depends upon the amount cf chlorine in the substance, 
is furnished by the chlorine derivatives of glycerine. Glycerol 
itself is inert, but the chlorhydrins have a narcotic action, and 
dilate the blood-vessels, this effect being the greatest in the 



24 • SYNTHETIC DRUGS 

case of trichlorhydrin, CHjCl— CHCl— CH^Cl, and least in the 
case of monochlorhydrin, CH2CI— CH(OH)— CH2OH. 

This fact is also illustrated by methyl chloride, CHgCl, 
methylene dichloride, CHjClg, chloroform, CHCI3, and carbon 
tetrachloride, CCI4, a series in which increase in the amount of 
chlorine is accompanied by increased narcotic action and in- 
creased toxicity. But in the case of the chlorinated fatty acids, 
the toxicity decreases with increase of chlorine, trichloracetic 
acid being practically non-toxic, while monochloracetic acid is 
strongly poisonous. The chlorinated fatty acids are also anoma- 
lous in another respect, as the narcotic action of the sodium 
salts of the fa^tty acids increases with rise of molecular weight 
from acetic acid to valerianic acid, while in the case of the 
corresponding chlorinated acids it diminishes with increase of 
molecular weight. 

In chloro-caffeine, there is an antagonism between the tonic 
effect of caffeine on the heart and the depressant action of the 
chlorine, and it is found that the tonic effect of this substance 
is less than that of caffeine, but the diuretic effect and the 
stimulation of the brain due to caffeine are not affected. 

> 

The entrance of halogen into the benzene nucleus produces 
only a slight change in the physiological properties. None of 
these derivatives have an ansBsthetic or hypnotic action, but 
there is usually an increase in antiseptic power. In general, 
there is a close resemblance between bromine derivatives and 
those of chlorine, both in the aliphatic and aromatic series. 
Organic iodine compounds differ from those of the other halo- 
gens in respect of their increased antiseptic power and their 
diminished hypnotic properties. (Compare chloroform, bromo- 
form, and iodoform.) The toxicity of the iodine compounds 
markedly exceeds that of the analogous chlorine and bromine 
compounds, but this has not seriously hampered their use as 
antiseptics, and a very large number of iodine compounds have 
been produced for this purpose. 

Effect of Nitre and Nitroso Groups. — ^The entrance of a 
nitro (NO2) or nitroso (NO) group in general causes a marked 
increase of toxicity, independently of whether it replaces a 
hydrogen atom in the nucleus or one in a hydroxyl group. 

The aliphatic nitrites give rise to dilatation of the blood- 



{the effect of various ^elements and radicles 25 

vessels, and are therefore used to lower the blood-pressure. 
The strength of this effect diminishes in descending the series 
from amyl nitrite to methyl nitrite. All the nitrites act in this 
manner, the secondary and tertiary being stronger in their 
action than the primary, probably owing to the fact that they 
are more readily hydrolyzed to alcohol and nitrite. A similar 
action is shown by the esters of nitric acid, nitro-glycerin, 
CHjCONOa)— CHCONOg)— CH2(0 . NO2), and erythrol tetra- 
nitrate being largely used in medicine to dilate the blood- 
vessels.^ 

Aliphatic nitro-compounds, such as nitro-methane, which are 
isomeric with the alkyl nitrites, 

K— Nf or R— N<: j K— 0— N=:0 

Nitro-compound. Nitrite. 

differ from them in their physiological action, being poisonous, 
but without the property of dilating the blood-vessels. 

The entrance of a nitro group into aromatic compounds 
usually increases the toxicity, nitro-benzene, nitro-naphthol, and 
nitro-thiophene, for example, all being more poisonous than the 
substances from which they are directly derived. Paranitro- 
NO2 



^Q,i 




toluene, [ J , is not very poisonous, because it is oxidized to 

j para-nitro-benzoic acid, [ J , which is then eliminated as para- 

lOOH 
NO2 

nitro-hippuric acid, I . As is usually the case, the entrance 

CO— NH— CH2— COOH 
of negative groups diminishes the toxicity, the aromatic nitro- 
aldehydes being non-poisonous, as they are readily oxidized to 
the inert nitro-acids. 

1 The workers employed in explosive factories often sufier from headache 
caused by the vapour of nitro-glyoerine ('* N.G.** headache). 



26 SYNTHETIC DRUGS 

Effect of Basic NitrosT^n Groups. — The entrance of basic 
nitrogen radicles into aliphatic or aromatic compounds, or the 
presence of nitrogen in cyclic bases, can produce very important 
pharmacological effects. The nature of these varies greatly in 
different cases, and at this point only a few features of interest 
will be referred to, as the subject will be considered from time 
to time in the special part of the book. 

The convulsive action of ammonia and its disappearance on 
the entrance of alkyl groups has already been referred to. Ee- 
placement of the hydrogen of ammonia by acid groups also 
diminishes the activity of the substance, and produces inert 
compounds which are found unchanged in the urine. 

For example : 

Garbamic acid, NHg — CO — OH, is poisonous, probably on 
account of its unstable charact§r, but its ester (urethane), 
NSj — CO — OCgHg, is more stable and has a hypnotic action. 

Hydrazine, NH2 — NH2, is far more toxic than ammonia, 
but the tetra- and penta-methylene diamines, Nn2[CH2]4NH2 
and NH2[CH2]5NH2, are quite non-toxic. Hydroxylamine, 
NH2 — OH, is very toxic on account of its reactivity with 
aldehydes (Loew's theory), and hydrazoic acid and its sodium 
salt are very toxic. The action of oximes resembles that of the 
aldehyde from which they are derived together ,with that of a 
nitrite, the =NOH group probably being oxidized to a nitrite. 

Acetoxime lowers the blood-pressure and has a narcotic 
action. 

Guanidine is toxic, owing to the presence of the labile imino 

(NH) group, HN=C<r ; and cyanamide, CN — NHj, has a 

^NH2 

toxic action similar to that of guanidine. 

The salts of the platinum-ammonium bases of the type, 
(NHJs^^Clg, resemble the other ammonium bases in having a 
curare-like action.^ 

Very great interest is attached to the experiments that 
have been made on the effect of the entrance of an amino 
group into the benzene nucleus, as they form the basis of a 
large number of antipyretics and analgesics. Amino-benzene 

^ Hofmeister, A. e. P. P., 16 (1883), 893. 



THE EFFECT OF VARIOUS ELEMENTS AND RADICLES 27 

(aniline) resembles ammotiia in- many respeots as regards its 

physiological action, but it also resembles benzene in some of 

ltd properties. It causes convulsions, but also paralysis of 

muscles and nerves, and if one of the hydrogen atoms of the 

amino group be replaced by an alkyl group, the convulsions no 

longer appear, but only the paralysing effect remains; If one 

of the hydrogen atoms in the nucleus of the aniline molecule be 

replaced by a simple atom, such as bromine, the convulsive effect 

is retained, and if it is replaced by an alkyl* group the effect is 

increased ; but if a complex group, especially an acid group, 

enters the nucleus, the effect is lost, as for example in amino- 

/NH2 
benzene-sulphonic acid, GqH.^<^ , Another property of all 

\SO3H 

these derivatives, such as aniline, is that they have a strong 
toxic action on the blood, forming methaemoglobin. The 
entrance of a second amino group into the benzene nucleus 
causes a great increase in the toxicity, all three phenylene- 
diamines, C^H^ (NH2)2, being extremely poisonous. 

While all the aromatic derivatives of ammonia and hydra- 
zine possess the property of lowering the temperature of the 
body, alicyclic-tetrahydro-)8-naphthylamine, 

CH CH2 
HC/\/'\CH— NH2 

G 
C 

H0\^\/CH2 
CH CH2 

produces a marked rise in the body temperature, and an increase 
in the albumin-metabolism. Substances containing tertiary 
nitrogen are often only slightly toxic, and are frequently with- 
out any effect at all. In many cases, if the tertiary nitrogen is 
changed into secondary by reduction, powerfully active sub- 
stances are obtained. 

The change of compounds containing tertiary nitrogen into 
substances with a curare-like action on conversion into am- 
monium bases has been mentioned in the previous chapter, and 
will be considered again in connection with the alkaloids. 

Effect of the Cyanogen Radicle. — Hydrocyanic acid, HON, 



28 SYNTHETIC DRUGS 

is well known as an exceptionally strong poison, and this fact 
is probably connected with its great chemical reactivity. The 
action of cyanogen is similar, but only about one-fifth as power- 
ful. In general, the isocyanides (isonitriles) cause paralysis of 
the respiratory centre, and the true cyanides (nitriles) produce 
coma. In this respect, therefore, the behaviour of hydrocyanic 
acid resembles that of an isocyanide (ENC) rather than that of 
a true cyanide (BCN). Neither the nitriles nor the isonitriles, 
however, show the intensely poisonous action of HON, this 
only becoming apparent when HCN is again liberated by the 
organism. The lower members of the series of fatty nitriles, 
CH3 — ON and CgHg — CN, are less poisonous than the higher 
members. Cyanacetic acid, ON — CHg — COOH, is practically 
non-toxic. Cyanogen chloride, CN — CI, is very poisonous, as 
it readily yields HCN. 

Potassium sulphocyanide, KCNS, is weakly poisonous for 
warm-blooded animals, but sodium nitroprusside, 

Na2Fe(CN)5NO. 

causes death with the appearance of prussic acid poisoning. In 
sodium ferrocyanide, Na^Fe(CN)g, neither the iron nor the CN 
group has any physiological action, and sodium platinicyanide 
shows no poisonous effect, though the ordinary platinum salts 
are very poisonous. 

Effect of Aldehyde Groups. — ^The physiological action of 
aldehydes appears to be closely related to their chemical re- 
activity. Formaldehyde, H . CHO, is very reactive, and has 
a strong irritant action on the mucous membranes, together 
with powerful antiseptic properties and a hardening action on 
the tissues. Acetaldehyde, CHg .CHO, shows the action of the 
aldehyde group combined with that of the methyl group, as it 
produces an excitation followed by ansBsthesia. The action of 
its polymeride, paraldehyde, (C2H^O)3, is stronger and more 
continued, and that of the higher polymeride, metaldehyde, 
(C2H40)», is more toxic. 

By the entrance of hydroxyl groups into the aldehyde mole- 
cule, and also by the condensation of these substances to form 
aldols, the reactivity of these bodies is appreciably depressed, 
and so also is >heir physiological action. The sugars, for 



THE EFFECT OF VARIOUS ELEMENTS AND RADICLES 39 

example, are physiologically inert. Most of the aromatic alde- 
hydes are of low toxicity, as they are readily oxidized to the 
corresponding acids, which are usually very inert. It is only 
in the case of strongly irritant substances that poisonous 
properties appear, owing to their action on the mucous mem- 
brane. 

Effect of Ketones. — The ketones in general possess phar- 
macological properties similar to those which characterize the 
corresponding alcohols, i.e. they bave a narcotic action. In 
the case of the aliphatic ketones this is fairly well marked, 
on account of the alkyl groups, and a hypnotic action is 
also shown by the mixed ketones, such as acetophenone, 
CgHg — CO — CH3 (hypnone). A large number of hypnotic 
substances of a more complex constitution contain a ketonic 
group, usually together with an ethyl group. These will be 
discussed in the section dealing with the hypnotics. 

Effect of Acid. Groups. — It has already been pointed out 

how the entrance of acid groups into the molecule causes a 

marked decrease or a total cessation of the physiological action. 

Phenol, CgHg — OH, is poisonous, but phenyl-sulphuric acid, 

CgHg — — SO2 — OH, is harmless. Morphine has a very 

powerful physiological action and is very poisonous, but 

morphine-sulphuric acid is quite inactive. In both these cases 

the diminution of the physiological effect is accompanied by 

the disappearance of a free hydroxyl group, the hydrogen of 

which is replaced by the SOg — OH group. It might therefore 

be thought that this change is due to the removal of the 

anchoring group, but the entrance of acid groups has the same 

effect in many substances where it produces no change in the 

anchoring or active group. For example, substances containing 

a nitro group are strongly poisonous, but the entrance of acid 

groups lowers or destroys the toxicity without altering the 

nitro group. For example, Martins yellow (dinitro-naphthol) 

is markedly toxic, but its sulphonic acid (naphthol yellow S) 

is harmless. Nitrobenzene, CgHg — NOg, is poisonous, but nitro- 

/NO, 
benzoic acid, CoEi.f , is harmless. It does not matter 

\COOH 

whether the sulphonic acid group is united to carbon or to 




30 SYNTHETIC DRUGS 

.OH 
oxygen, both CeHg— O— SOg— OH and CeH4<; being 

^SOjj . OH 

innocuous. 

The entrance of carboxyl (COOH) groups into the aromatic 

nucleus is of great importance from the point of view of the 

synthesis of drugs, as it generally lowers the toxicity so very 

much. Benzene itself can be tolerated in doses of eight grams 

per day, but from twelve to sixteen grams of benzoic acid per 

day can be eliminated by the organism as hippuric acid, and 

still larger quantities can be administered without toxic effects, 

the excess being eliminated unchanged.^ Aniline, which is 

more toxic than benzene itself, is rendered practically harmless 

by the entrance of a carboxyl group, meta-amino-benzoic acid, 

, being well tolerated by the organism. 

!00H 

On the other hand, physiological properties which have been 
lost by the entrance of acid groups can be restored if these 
groups are esterified. ' For example, tyrosine, 

COOH 
H0< >CHg— OH 

NH, 

is not poisonous, but the hydrochloride of its ethyl ester has been 
shown to be strongly poisonous when administered to dogs.^ 

The addition of acid radicles to active basic substances is 
of special importance for the preparation of synthetic drugs. 
This is especially the case with regard to the acetylation of the 
amino group. By this means, the basicity is weakened and 
the action of the substance retarded, as it is only after hydrolysis 
that the active basic portion of the compound becomes free 
to exhibit its physiological effect. The acid group is usually 
physiologically inert, and the choice of the particular acid 
group to be used to combine with the amino group is governed 
chiefly by the physical properties of the compound thus formed. 

* Nencki, A. e. P. P., 30 (1892), 300. 
*Kohn, Zeit. physiol. Chem., 14 (1890), 189. 



THE EFFECT OF VARIOUS BLEHENTS AND RADICLES 31 

Lactyl derivatives are, as a rule, more soluble than acetyl, 
and these in their turn ^ are more soluble than benzoyl, while 
salicyl derivatives are usually almost insoluble. Now, in most 
cases the speed of hydrolysis depends chiefly on the solubility 
and hence the rapidity with which a drug of this type acts 
depends on the acid group, but the nature of the action is 
usually not affected thereby. Usually, acetyl derivatives are 
the most convenient, not only because they are the cheapest to 
prepare, but also because the lactyl derivative is sometimes too 
rapidly hydrolyzed, whilst the benzoyl derivatives are generally 
hydrolyzed so slowly that they are excreted largely unchanged, 
and therefore without having exerted the desired effect. The 
only one of the previously mentioned acids that has a marked 
physiological action of its own is salicylic acid, but the salicyl 
derivatives of basic compounds are so insoluble that they 
usually escape from the organism almost entirely unchanged, 
and therefore are therapeutically useless. 

The presence of the benzoyl group is of great ipaportance in 
a large number of substances, especially in some of the alkaloids. 
Ecgonine methyl-ester is without any noteworthy action, but 
its benzoyl derivative, cocaine, has a very important physio- 
logical action, producing local ansBsthesia and other powerful 
effects. These facts are discussed in another section, so need 
not be enlarged upon at present. 

Effect of Unsaturated Linkages. — Unsaturated com- 
pounds are usually far mpre toxic than the corresponding 
saturated ones, a fact which is in accordance with their 
greater chemical reactivity. For example, propyl alcohol, 
CH3 — CH2 — CHg — OH, is a narcotic, and causes intoxica- 
tion, but is not really poisonous, -whereas allyl alcohol, 
CH2=CH — CHj — OH, has strong poisonous properties, but 
is without the narcotic action which is characteristic of the 
saturated alcohols. Indeed, the unsaturated alcohols are dis- 
tinguished by their highly poisonous charq,cter. 

Safrole, 




CH2^CH — GH2 



'8 



32 SYNTHETIC DRUGS 

is far more poisonous than any other ethereal oil that has been 
experimented upon, and the isomeric compound, iso-safrole, 

CHg 
is also poisonous, but not so strongly as safrol. Menthone is far 

L A 

HjC CO HC CO 

\/ \/ 

CH CH 

CH C 

X\ ^\ 

CH, CH, CHg CHj 

Menthone. Carvone. 

less toxic than carvone, which differs from it bnly in contain- 
ing two unsaturated linkages, and acrolein, CH2=CH — CHO, 
and crotonic aldehyde, CH, — CH=CH — CHO, are far more 
toxic than the corresponding saturated compounds. 

The influence of increasing unsaturafion is well illustrated 
by the following series of compounds : — ^ 

CHj CHjj— CH2— OH 

\/ 
CH,— N 

/\ 
CH, OH 

Choline (slightly toxic). 

GSg Gil = GM2 CH3 G— GH 

\/ \/ 

CH3— N CH3--N 

/\ /\ 

CH3 OH CH3 OH 

Neurine (very toxic). Far more toxic than neurine. 

AUyl-tri-methyl-ammonium hydroxide, 

^ Schmidt, Annalen, 267 (1892), 249. 



THE EFFECT OF VARIOUS ELEMENTS AND RADICLES 33 

OH 

(CH3)3=N 

\ 
CS2 — CIi= CHg 

a homologue of neurine, is exceptional in being only slightly 
poisonous. 

Effect of Molecular Weight, Isomerism, etc. — Polymer- 
ides often show a different action from that of the original sub- 
stance, but up to the present no regularities have been observed. 

The effect of increasing molecular weight in the series of the 
paraffins and the alcohols has already been referred io. In the 
substituted ureas, the narcotic effect increases with the number 
of carbon atoms in the branched side chain in the same way as 
it does in the alcohols, and a similar effect is found in the case 
of the pinacones. 

The fatty acids are generally innocuous. Oxalic acid is 
poisonous, but the toxicity rapidly diminishes as the series is 
ascended. In the case of the homologues of pyridine, the toxi- 
city increases very rapidly with increase of molecular weight. 
Pyridine, C5H5N, is the weakest in its action, and the intensity 
of toxic effect increases as the series is ascended through pico- 
line, lutidine, and coUidine, to pajvoline, 05HN(CH3)4, which 
is eight times as strong in its action as pyridine. 

There is often a surprisingly great difference in the activity 
of stereo-isomerides. Isopilocarpine is probably stereo-isomerio 
with pilocarpine itself,^ but it is far weaker in its physiological 
action. Maleio acid is toxic for dogs, but its stereo-isomeride, 
fumaric acid, is said to be harmless.^ 

COOH 

'H— 0— COOH^ 
H— C— COdH, 

B.IL ICOOH 

Maleio acid. 

1 Jowett, /. C. S., 87 (1905), 794. 

^Ishizuka, Bull Coll, Agr, Tokyo, 2 (1897), 484. 

3 





34 SYNTHETIC DRUGS 

COOH 



H— C— COOH' 

II 

HOOC— C— H 
HOOC£ \H 

Famario aoid. 

The difference may, however, be due to the different degree 
of ionization, maleio aoid being the more highly ionized of the 
two. 

In the case of stereo-isomerides, which are optically active, 
marked differences in the pl\yBiological action are very often 
encountered. At this point it will suffice to mention briefly 
a few examples. Atropine (racemio hyoscyamine) differs in 
some respects from 2adt70-hyoscyamine,^ and laevo-niooiine is 
twice as poisonous as the dextro variety.^ One of the most 
striking examples of this type is that of adrenaline, the natural 
laevo form being about eleven or twelve times as active as the 
dextro.^ Optical isomerides sometimes show differences in 
taste or smell, (^erc^ro-asparagine, for example, being sweet, 
and 2a«i;o-asparagine tasteless.^ 

The change in physiological properties which accompanies 
the change from a plane to a spatial configuration in the case 
of certain compounds of nitrogen, phosphorus, arsenic, and 
sulphur, is discussed in Chapters I. and VI. 

Differences are often met with in the physiological action of 
ortho, meta, and para compounds, and in some types of com- 
pounds regularities can be traced. It has been suggested that 
para compounds are more poisonous than ortho,'^ and this is 
often the case, but in many compounds the reverse is true, 
ortho nitro-benzaldehyde, for instance, being more toxic than 
para. In fact, although many differences have been noted 
between the physiological effects of isomeric benzene deriva- 

'OuBhny, Joum. of Physiol, 30 (1904), 193. 

'jMayor, J5«r., 38 (1906), 697. 

"Oashny, Joum. of Physiol,, 38 (1908), 269. 

*JPiutti. C. B., 103 (1886), 134. 

^akorny, Joum. prakt. Chem., 36 (1887), 272. 



THE EFFECT OF VARIOUS ELEMENTS AND RADICLES 35 

tives, no general regularities have been traced between the 
ortho, meta, and para compounds, and between the different 
tri-substituted derivatives. 
In this connection it is interesting to note that saccharin, 

which IS an ortho compound, [] NH, is five hundred 

times sweeter than sugar, while the corresponding para com- 
pound is tasteless. Some ingenious theories have been ad- 
vanced to account for the sweet taste of certain compounds, 
but they are none of them very satisfactory and call for no 
detailed account. 

Closely related isomerides, other than benzene position- 
isomerides, often show remarkable differences in their physio- 
logical action. Cocaine differs from its isomeride a-cocaine 
only in having a ( . CO . OCHg) group and a ( . O . CO . CeHg) 
group on adjacent carbon atoms, while in a-cocaine these 
groups are on the same carbon atom. Nevertheless, a-cocaine 
.IS lacking the characteristic local anaesthetic action'of cocaine 
itself (Chapter VII.). 



3* 



CHAPTEK III. 

THE CHEMICAL CHANGES OP DRUGS IN THE ORGANISM. 

Very valuable information can often be obtained by a study 
of the changes which a substance undergoes in the animal 
body. By this means an insight into the mode of action of 
a .drug can often be obtained, and a method of preparing and 
using a less toxic substance can often be devised, owing to the 
fact that the usual alteration of drug^by the metabolic pro- 
cesses in the organism is in the direction of the conversion of 
an active and poisonous drug into a less active and less poison- 
ous one. This is usually accomplished by the production of 
bodies of a more acidic character than the original substance. 
In some cases this is brought about by a simple process of 
oxidation, but more often a substance is formed, usually by 
oxidation but sometimes by reduction, which is then trans- 
formed into an inert salt of an acid by means of a synthetic 
process. The most important of these synthetic processes 
taking place in the organism are union with sulphuric acid, 
glycuronic acid or amino-acetic acid. Before considering these 
synthetic processes, attention must be given to the changes 
which precede them, by means of which substances are formed 
which are capable of readily uniting with sulphuric acid, 
glycuronic acid, etc. 

The chemical processes taking place in the organism consist 
of hydrolytic cleavages (saponification of esters, etc.) in the 
alimentary canal, and more profound changes of oxidation, and 
sometimes reduction, in the tissues or blood. In the case of 
the changes taking place in the alimentary canal, it is found 
that the saliva acts on but few drugs, owing to the short time 
that they remain in contact with it, and the fact that only one 
enzyme — diastase — is present. The contrary is the case in the 
stomach, in which many drugs can be absorbed, and where 

36 



CHEMICAL CHANGES OF DRUGS IN THE ORGANISM 37 

unpleasant by-eifects are often manifested. For this reason, a 
great proportion of the work in connection with the synthesis 
of new drugs consist in modifying previously existing com- 
pounds so that they are rendered incapable of being absorbed 
or of exerting any action in the stomach. The gastric juices 
contain hydrochloric and other acids, and also an enzyme, 
pepsin, but it is to their acid character that their action on 
drugs is mostly due. Salts of organic acids are generally de- 
composed into the free acid and a chloride of the base, but 
esters and similar compounds are, in the great majority of 
cases, undecomposed by the gastric contents. 

In the small intestine, substances enter an alkaline medium 
and come into contact with the pancreatic enzyme, trypsin. 
The latter has a marked hydrolyzing action on esters, anilides, 
and similar bodies, and it .is only those substances which are 
hydrolyzed with great difficulty by all ordinary reagents that 
escape hydrolysis in the intestine. After saponification in the 
intestine, the components are able to exert their specific action, 
and advantage is taken of this fact in preparing derivatives the 
components of which would exert unpleasant by-effects on the 
stomach, but which remain undecomposed in that organ, and 
are then hydrolyzed in the intestine, enabling the components 
to exert their desired effect. 

For example, salicylic acid and its salts often give rise to 
unpleasant symptoms in the stomach, but acetyl-salicylic acid 
is comparatively inert and passes through the stomach un- 
changed. In the intestine it is hydrolyzed into sodium sali- 
cylate, which can then exert its useful action, and sodium 
acetate, which is inert. 

Most aliphatic substances are oxidized to carbon dioxide, 
water, and urea, but there are numerous exceptions. Many 
substances are oxidized to acids, but aldehydes are never 
formed by oxidation in the body. On the contrary, alde- 
hydes are often reduced to the corresponding alcohol, chloral, 
CCI3 . CHO, for example, being reduced to trichlorethyl alcohol, 
CCI3 . CHg . OH.i Many substances containing methyl groups 
are oxidized with difficulty; isopropyl alcohol is said to be 

iZeit, physiol Chem., 6 (1882), 440; Ber., 15 (1882), 1019; PflUger's 
Archiv, 28 (1882), 506 ; 33 (1B84), 221. 



38 SYNTHETIC DRUGS 

partly oxidized to acetone and partly excreted unchanged; 
Acetone itself is oxidized with difficulty, methyl-ethyl-ketone 
more readily, while diethyl-ketone is almost completely oxid- 
ized.^ Primary and secondary alcohols are readily oxidized, 
but tertiary and all halogen-substituted alcohols are difficultly 
oxidized. Similarly, fatty acids are completely oxidized to 
carbon dioxide and water, but the chloro-substituted acids are 
not at all easily oxidized. 

Aromatic compounds are not so readily oxidized by the 
organism as the aliphatic compounds. In all but a few ex- 
ceptional cases, the aromatic nucleus remains unchanged, the 
process of oxidation being confined to the side chains. In 
those substances which contain a side chain of three carbon 
atoms, the middle one of which bears an amino group, the 
substance is completely oxidized. For example — 

phenylalanine, CeHg . CH2— CH— COOH 
tyrosine, H0< >CH^ . CH— COOH, etc.2 



NH, 



In dogs also, phthalic acid and phthalimide — 

yvCOOH /\C0. 

and >NH 

^COOH Vco/ 



are completely oxidized.^ Many aromatic compounds are oxid- 
ized in the organism by the entrance of a hydroxyl group in 
the para position to a previously present substituent group, but 
if the para position is already occupied, no hydroxylation takes 
place in the animal body. For example, aniline is oxidized 

to para-aminophenol,^ H0< ^ ^ NH^. Ortho compounds are far 
more readily oxidized than para or meta. Aldehyde groups 
are oxidized to carboxyl groups, and in general a substance is 
usually oxidized to a carboxylic acid if this process takes place 

1 Sohwarz, A, «. P. P., 40 (1898), 178. 

^ZeU. physiol. Chem., 7 (1882), 23; 8 (1883), 63, 65; 10 (1886), ISO; 
11 (1887), 486; 14 (1890), 189. 

sjuvalta, Zeit, physiol Chem,, 13 (1889), 26; Mosso, A. e. P. P., 26 
(1890), 267. 

*Schmiedeberg, A, e. P. P., 8 (1878), 1. 



CHEMICAL CHANGES OP DRUGS W THE ORGANISM 39 

at all readily. Toluene, for example, gives benzoic acid, but 
benzene, on the other hand, is oxidized to phenol.^ The fate of 
phenol and similar substances in the organism will be discussed 
later. 

Beduction of a substance in the organism sometimes takes 
place, although it is a much more unusual process than oxidation. 
An interesting example is furnished by chloral, GCI3 . GHO, 
which is reduced by the organism to trichlorethyl alcohol, 
CGI3 . GHj . 0H,2 a reduction which can only be carried out 
with extreme difficulty in the laboratory. Quinone is reduced 
to hydroquinone. Beduction of a nitro group to an amino 
group is exceptional, nitrobenzene, for instance, never being 
reduced to aniline, but this type of action sometimes does 
occur. For example, both meta- and para-nitro-benzaldehydes 
undergo reduction of the nitro group, accompanied by oxidation 
of the aldehyde group, the product finally formed by the organ- 
ism being the acetyl derivative of the corresponding amino 
acid — ^ 

.NO2 .NH2 .NH . GO . GH3 

^GHO \G00H ^GOOH 

Another interesting example of this type of change is furnished 
by ortho-nitrophenyl-propiolic acid, which is transformed by 
the organism into indoxyl, this being excreted as potassium- 
indoxyl-sulphate — * 

.NO2 NH NH 

^ GgH /\G-G00H ^ GeH,/\GH 

'\GsG— GOOH G G 

Indoxyl. 
Picric acid is partially reduced to dinitro-amino-phenol. 
GeH2(N02)30H -> GeH2(N02)2NH2 . OH.^ 
The final stage in the transformation of drugs into inert 

1 Dubois Arch. (1867), 340; PftUger's ArcMv, 12 (1876), 148. 

2 Zeit. phyaiol. Chem,, 6 (1882), 440 ; Ber., 15 (1882), 1019 ; Pflilger's 
Archiv, 28 (1882), 506 ; 33 (1884), 221. 

''R. Oohn, ZeU. physiol Chem., 17 (1898), 285 ; 18 (1894), 133. 
* Hoppe-Seyler, Zeit, physiol Chem., 7 (1882), 178. 
6 Walko, A. e, P. P., 46 (1901), 181. 



a. 



40 . SYNTHETIC DRUGS 

substances consists in the formation of acidic substances from 
the products of oxidation, reduction, etc., by means of the 
previously mentioned syntheses with sulphuric acid, glycuronic 
acid, etc. Other synthetic processes sometimes met with are 
the formation of urea derivatives and sulphocyanides, and more 
rarely, the introduction of acetyl or methyl groups, and the 
production of cystine derivatives. Usually no single synthetic 
process takes place to the exclusion of all others, but, on the 
contrary, a substance is usually excreted in more than one 
way, for example,' as a glycuronic acid derivative, and also as 
a sulphonic ester. 

Sulphonic Esters. — The sulphuric acid required for these 
syntheses may be formed by the oxidation of albuminous bodies 
containing sulphur. It has already been pointed out that 
phenolic substances are often formed by the oxidation of 
aromatic compounds, and most of these phenolic compounds 
are excreted primarily combined with sulphuric acid as alkali 
salts, and secondarily combined with glycuronic acid. Phenol 
itself is found in the urine as the sodium salt of phenyl- 
sulphuric acid, CgHg . . SO2 . ONa, a perfectly non-toxic sub- 
stance. Similar syntheses take place with other hydroxyl 
derivatives, but if these themselves are non-toxic, they are 
excreted unchanged without undergoing a synthesis with sul- 
phuric or glycuronic acids. For example, homogentisinic acid, 

OCHn.COOH 
, which is non-toxic, is eliminated un- 
OH 

/NCOOIJ 
changed, but the corresponding gentisinic acid, 1 

HO'\/'OH 

which is toxic, is eliminated partly as the non-toxic sulphuric 

acid derivative.^ The entrance of acid groups into phenols, 

with the corresponding loss of toxicity, destroys the property 

of combining with sulphuric or glycuronic acids, as in the 

case of salicylic acid, which is eliminated in combination 

with amino-acetic acid in the same way as benzoic acid {i.e. it 

forms a compound analogous to hippuric acid).^- Loss of acid 

character causes this property of combining with sulphuric 

1 Likhatschefi, Zeit. phy^iol. Chem., 21 (1896), 422. 
3 See this chapter, last section. 



CHEMICAL CHANCES OP DRU6S W THE ORGANISM '4*. 



•  - • 

acid to reappear, and methyl salicylate, 



/NCOOCH 
UoH 



and 



salicyl amide, 



/\C0 . NH. 



CHjO/NCOOH 

Veratric acid. 



^, are found in the urine as sulphuric 

acid derivatives.^ Introduction of more hydroxyl groups also 
causes this property to reappear, as in the case of gentisinic 
acid, and also protocatechuic and vanillic acids ; hut veratric 

HO/NCOOH CHgO/^COOH 
HoU H0'\/ 

Protocatechuic acid. Vanillic acid, 

acid, which contains no free hydroxyl, does not unite with sul- 
phuric acid. Aromatic ketones are usually oxidized to acids, 
but if they contain a hydroxyl group the formation of esters 
with sulphuric or glycuronic acids takes place, to the exclusion 
of the oxidation of the ketone to the corresponding acid. For 
example, acetophenone, CgH^ . CO . CHg, is oxidized to benzoic 
acid,^ but paeonol, gallacetophenone, and resacetophenone are 

OH 



/\C0 . CH, 



CH3O 



/\0 



\/ 



CO . ca 



/Nco . ca 



HOVOH 
OH 



HO 



\/ 



OH 



Paeonol. Gallacetophenone. Kesacetophenone. 

found in the urine as sulphuric and glycuronic acid deriv- 
atives.^ 

Qlycuronic Acid Derivatives. — This acid, which has the 
constitution CHO — (CH . OH)^ — COOH, is of great interest, as 
a very large number of poisonous substances are found in the 
urine as derivatives of it. It seems likely that in the first in- 
stance combination takes place between the drug and glucose, 
the — CHgOH group of which is then oxidized to COOH, with 
the formation of glycuronic acid. In the case of aliphatic 
compounds, the resulting compounds are formed with elimina- 
tion of water, and are probably analogous in structure to the 
simple glucosides. 

For example, chloral is reduced to trichlorethyl alcohol, 

1 Baumann and Herter, Zeit. physiol, Chem., 1 (1878), 255. 
'Nenoki, Journ. prakt. Che7H.;lS (1878), 288. 
8 J&id., Ber., 27 (1894), 2787. 



42 SYNTMBTtC DRUGS 

which then combines with glycuronic acid in the follovB^ing 
manner : — 

COOH COOH 

CH .OH CH . OH 

OH . OH CCl, -> CH . OH 

CH . OH + CHa CH . OH OH 



CH . OH— CHO OH CH . OH— CH 



CH— O— CH2— CCI3 



COOH 

I 
CH.OH 




CH . OH O 



CH . OH— C— 0— CH2— CCI3 

In the case of some aromatic compounds, combination can 
occur without the elimination of water. For example, it has 
been shown that vanillin is oxidized to vanillic acid, which 
then combines with glycuronic acid— 1 

COOH OH COOH 

(CH . OH)^ + CflHj— OCH3 = (CH . 0H)4 



i- ^ 



;H0 COOH /OH 

CH<: /COOH 

\o-c«H3<; 

\0CH3 

Thymol and carbostyril have been shown to behave in a 
similar manner. 

Derivatives of Amino-Acetic Acid. — Combination between 
glycine, NHj . CH^ . COOH, and benzoic acid takes place in the 
kidney, with formation of hippuric acid — ^ 

COOH COOH +H2O 



A_NH, + HO . CO . C«H, = H«C— ] 



HgC— NH2 + HO . CO . CgHfi = HgC— NH— CO . CgHg 

^Kotake, Zeit. physiol, Chem,, 45 (1905), 820. 
>Boucis and Ure, Berzelius' Jahretb,, 22 (1843), 567. 



CHEMICAL CHANGES OP DRUGS tN THE ORGANISM 43 

This synthesis is of great importance, as so many compounds 
are oxidized in the body to benzoic acid, and it is also typical 
of a large number of precisely similar syntheses undergone by 
other carboxylic acids, such as salicylic acid, para-hydroxy- 
benzoic acid, chloro-, nitro-, and bromo-benzoic acids, anisic 
acid, naphthoic acid, and many others. 

Other synthetic processes that may be mentioned are the 
formation of the .less toxic sulphocyanides from the toxic 
nitriles,^ the transformation of pyridine into methyl pyridyl 
ammonium hydroxide,^ 

CH CH 

N N 

CHg/XOH 

and the introduction of an acetyl group into a compound, as 
in the previously mentioned case of meta-nitro-benzaldehyde, 
which is transformed into meta-acetyl-amino-benzoic acid. 

1 A. e. P, P., 34 (1894), 247, 281. 

« His, A. e. P. P., 22 (1887), 258 ; B. Cohn, ZeU. physiol Chem., 18 (1894), 
112. 



CHAPTER IV. 

NARCOTICS AND GENERAL ANESTHETICS. 

Oenebal Theories op the Action of Nabcotic Drugs. 

Up to within quite recent times, the only narcotics in use were 
the various preparations of opium, and all of these suffered 
from the great drawback of being dangerous in the doses that 
were necessary to produce certain sleep, and of sometimes 
causing unpleasant by-effects. The discovery of many syn- 
thetic substances having a powerful narcotic action, and almost 
free from the dangers and other drawbacks of preparations 
containing morphine, is one of the great triumphs of the 
application of synthetic chemistry to pharmacology. 

Still more important are those substances which are used 
as general anaesthetics. These compounds do not differ funda- 
mentally from the other narcotics in their physiological action 
or chemical constitution, but they are usually volatile substances 
which are administered by inhalation, so that their effect can 
be rapidly produced, and the duration easily regulated. On 
the other hand, for use as a narcotic it is more convenient to 
employ non-volatile substances capable of offering resistance to 
oxidation by the organism, and which are therefore slower and 
more prolonged in their action. 

The aliphatic hydrocarbons possess narcotic properties, and 
these are increased by the introduction of an hydroxyl group 
to form alcohols. The introduction of more hydroxyl groups, 
as in glycerol, causes the narcotic action to disappear, the 
hydroxyl merely playing the part of an " anchoring " gfoup. 
On the other hand, the narcotic action of many different 
substances is associated with the presence of alkyl groups, 
especially ethyl groups. It therefore appears that in the 
alcohols, the alkyl group, and not the hydroxyl group, is the 

44 



NARCOTICS AND GENERAL ANESTHETICS 45 

active portion of the molecule. Eeplacement of hydrogen 
atoms in a hydrocarbon by halogen, and especially by chlorine^ 
also greatly increases the narcotic action of the substance, and 
in these cases the chlorine actually seems to play an important 
part in the action of the substance, because unlike the case 
of the alcohols, the strength of the action tends to increase with 
an increase in the number of chlorine atoms in the compound. 
This narcotic property is characteristic only of the aliphatic 
halogen compounds ; in the case of the halogen derivatives of 
benzene it is absent. 

The inhalation general anassthetics comprise, therefore, two 
groups, those in which the action is associated with the presence 
of halogen in aliphatic combination, and those in which it is 
associated only with the presence of alkyl groups. The narcotics 
likewise include substances of these types, and also many com- 
pounds, the narcotic action of which seems to be connected 
with the presence of the carbonyl group ( — CO — ) in the 
molecule, and in some cases With the presence of a ring system 
containing basic nitrogen. 

The foregoing statements will show that the ansBsthetics 
and narcotics comprise a number of substances, which, from 
the chemical point of view, have really very little in common. 
Attempts have therefore been made to find a relation between 
some of the physical properties of these substances, and as a 
result, some interesting facts have been brought to light, which 
tend to show that in many cases there is a close parallelism 
between the hypnotic action and certain physical properties of 
the substance. Not only is this the case, but these physical 
theories of narcosis are superior to any purely chemical theory 
that can be devised, in that they throw some light on the mode 
of action of the hypnotic substances. 
r'^'^^This is well illustrated by the work of Overton,^ and the**^ 
I suggestive theory that has been put forward by Hans Meyer .^ [ 
I It has been shown by Overton that substances may be * 
divided into different groups according to the rapidity with 
which they diffuse into protoplasm, the rate of diffusion as a 
general rule depending on the solubility of the substances in 

* ** Studien uber Narkose," Jena, 1901. 

2 Hans Meyer, A. e. P. P., 42 (1901), 109 ; and 42 (1901), 119 (Baum). 



46 



SYNTHETIC DRUGS 



fat, lecithin, and *' lipoid " substances of that type. If S/ denotes 
the solubility of a substance in fat, and 8„ that of the same 

substance in water, then the ratio ^ is called the distribution 

— — — — o^p — 

coefficient of the substance, and according to Overton, the 
value^of this coefficient determines the"T6l'6city^ of diffusion 
into^the cell protopT^sm. Now, it was pointed out by Overton 
and Meyer that ansBsthetics and narcotics are generally sub- 
stances which diffuse rapidly, and therefore these compounds 
should possess a high distribution coefficient. Meyer compared 
the aliphatic narcotics, an d found that the narcotic power of 
thes e was roughly proportional to . jih&. ^agnitude of th e dis- 
tri bution coefficient. This fact is sometimes expressed by 
saying that the strength of the narcotic action of a compound 
is depende nt on its solu bility in lipoid substance'. "'Tfi!r4s not 
strictly true, as it depends noF so much on its actual solubility 
in the li poid substance as upon the ratio of its solubility in 
lipoids to that of its solubility in water. 



Substance. 



Dimethyl-sulphone-dimethyl-methane^ 
Diethyl-sulphone-nlethane ^ . 

Sulphonal 

Trional 

Tetronal 

Butyl-chloral-hydrate .... 
Bromal-hydrate . . ... 
Chloral-hydrate . . . 

Ethyl-urethane 

Methyl-urethane 

Monacetin 

Diacetin 

Triacetin 



Liminal 
Value. 


Distribution- 
coefficient. 




0-106 




0-161 


0-006 


1-116 


0-0018 


4*46 


0-0013 


4-04 


0-002 


1-59 


0-002 


0-66 


0-02 


0-22 


0-04 


0-14 


0-4 


0-04 


0-6 


0-C6 


0-016 


0-23 


0-010 


0-30 



Narcotic Action. 



Very slight. 
Slight. 
Marked. 
More marked. 

It 

II 

I* 

II 

II 

II 

II 

II 

»» 



Meyer compared the narcotic power of these substances by 
finding the smallest concentration which would produce a 
definite physiological effect, andex pressed the values ^s fractions 
of the normal solution (one gram moL Htre), 6alIIng these the 



1 (0H,)3C(S02 . CH3),. 



a CHj(S02 . CaHg)^. 



NARCOTICS AND GENERAL ANESTHETICS 



47 



" liminal valnes. " These "liminal values" can be taken as 
being approximately inversely proportional to the strength of 
the narcotic action. ^ On comparing them with the distribu- 
tion coefficient, it is found tl^at thay jrAry in f.hft^nppnaif.A 

direction, being small when the distribution coefficient is large, 
and these results therefore indicate that the strength of the 
narcotic action of these substances is approximately propor- 
tional to the distribution coefficient. 

In the preceding table the substances are arranged together 
in accordance with their chemical nature, but in order to show 
the close parallelism of the narcotic effect and the distribution 
coefficient, it is worth while arranging them in order of magni- 
tude. 



Substance. 


IHstribntion- 
coefficient. 


Liminal Value. 


Trional 

Tetronal .... 

Butyl-chloral-hydrate 

Sulphonal 

Bromal-hydrate 

Triacetin .... 

Diacetin . 

GhlonJ-hydrate 

Ethyl-urethane 

Monacetin 

Mothyl-urethane 




• • 


4-46 
4-04 
1-59 
1-11 
0-66 
0-30 
0-23 
0-22 
0-14 
0-06 
0-04 


0-0018 - 

0-0013 

0-002 

0006 

0-002 

0-010 

0-015 

0-02 

004 

0-05 

0-4 



The substances are here given in order of decreasing dis- 
tribution-coefficient, and it will be seen that with two slight 
exceptions, the liminal values of the substances, given in the 
same order, steadily increase. This result is of great interest, 
especially as the substances tabulated above represent many 
widely different chemical types. In the case of the sulphone 
derivatives, a high distribution-coefficient seems to be con- 
nected with the presence of ethyl groups, and it had already 
been pointed out by Baumann and East that the narcotic 
properties of these compounds depended on the ethyl groups. 
This will be referred to in greater detail in connection with 
these compounds. 

Not only is the theory of Overton and Meyer well supported 
by the close parallelism shown above, but numerous subsidiary 



48 SYNTHETIC DRUGS 

facts appear to give it additional support. One of these is an 
observation by Mansfeld^ that some narcotics have a more 
powerful action when given to starved animals, the explana- 
tion suggested being that in these there is less tissue-fat to 
absorb some of the narcotic, so that a greater portion of the 
latter is absorbed by the central-nervous system. No doubt, 
however, an alternative explanation could be offered. 

There are nevertheless a good many facts appearing to show 
that this theory is incomplete and needs some modification, 
before it can be applied to all cases. For example, the peri- 
pheral nerves contain a large amount of ** lipoid '' substance, 
but they are much less affected by the aliphatic narcotics. 

It has also been pointed out by Cushny' that many aro- 
matic compounds have a high distribution-coefl&cient, but are 
without narcotic action f^^A^ possible e xplanation of these facts 
is suggested by the vie ws of Traube , according to which it is 
th e osmotic permeability of a substance which is of p rimary 
impor tance in determinin g its narcotic actio n. In support of 
this view, it is pointed out that pyridine, ni cotine , and anti- 
pyrine rapidly penetrate the membranes, altho ugh t heir dis- 
tribution^coefficients are le ss tEan unity. Tra.i]{ifl Ann^riftra |lmt. 
s urface tension is the force producin g osmosis, and he there fore 
^^"^^ijflfi thftt mirfp/*^ tension and narcotic powershouldrun 
paralle l. This was found to be the case with a large number 
of narcotics of varied types. It certainly seems reasonable 
to su ppose that rapid penetration of jhe^c^Us ^houi y be the 
most essential condition for enabling a su bstance to exert its 
effect nn jb« inte rior gf'Dliose ce lls. When the substance has 
once gained an entrance into the cell, its solubility in the cell 
"lipoids'* may be an important factor iETdetermining its nar- 
cotic power7~jCChe theories of Traube and Overton- Meyer are 
therefore not altogether antagonistic, and both of them are 
probably concerned with important facts underlying the mode 
of action of hypnotic substances. 

Moore and Eoaf ^ have studied the solubilities of chloroform 

1 Mansfeld, GentraXbL fUr Physiol,, 20 (1906), 664. 
8 *' Text-book of Pharmacology," p. 128. 1904* 

» Moore and Roaf, Proc, Boy, Soc,, 73 (1904), 382; Proc, Boy. Soc. J5., 
77 (1906), 86. 



NARCOTICS AND GENERAL AN /ESTHETICS 49 

and certain other ansesthetics in solutions of blood serum and 
hsBmoglobin^ and have found them to be considerably higher 
than in ordinary saline solution or in pure water. The curves 
connecting the vapour-pressure and concentration of chloroform 
in serum or haemoglobin solutions do not correspond to the 
normal behaviour of a simple solution, but show evidence of 
association between the solvent and the dissolved substance* 
Moore and Eoaf therefore consider that anaBsthetics form un- 
stable compounds or aggregates with the proteins of the tissue 
cells, which exist only so long as the partial pressure of the 
anaBSthetic in the blood is maintained, and that anaesthesia is 
due to a paralysis of the chemical activities of the protoplasm 
as a result of the formation of such aggregations. The curves 
obtained do not point to the formation of definite chemical 
compounds, but are more of the nature of adsorption curves. 

The action of certain substances, such as alcohol, cannot be 
explained by the foregoing theories. Alcohol is miscible with 
water in all proportions, and is only slightly soluble in fats,. 
but this need occasion no surprise when it is borne in mind 
that alcohol does not really belong to the same class of sub- 
stances as sulphonal and inert bodies of that type, as it exerts 
some action on proteins and is oxidized in the body. The 
action of alcohol is, therefore, probably specific, and of a dif- 
ferent kind from that of sulphonal, etc. 

A theory, according to which narcosis is due to deprivation 
of oxygen, has been suggested by Baglioni.^ It is based on 
the fact that in the case of various aromatic compounds, the 
paralysing action of the substance is inversely proportional to 
the amount of oxygen already in the side chain, and that de- 
privation of oxygen by breathing inert gases, such as carbon 
dioxide, produces symptoms not unlike those of chloroform 
narcosis. In support of this view, it might be pointed out that 
Herter has shown that chloroform,. ether, and chloral-hydrate 
diminish the oxidizing capacity of the tissues. This hypothesis 
indicates a possible mode of action of the narcotics after they 
have once entered the cell, the preceding theories indicating 
the conditions which determine their entrance into the cell 
substance. 

^ Baglioni, Zeitschr. allg. Physiologie^ 3 (1903), 318. 

4 






50 SYNTHETIC DRUGS 

Halogen An-esthetics and Hypnotics. 

The most widely used compound of this type is chloroform, 
which shares with ether the distinction of being the most 
widely used ansBsthetic. The deaths that' occasionally take 
place when chloroform is used may in some cases be due to 
decomposition products such as phosgene, but it was formerly 
thought that these were impurities present in the chloroform 
to start with, and hence methods were devised to purify the 
chloroform very carefully when it was manufactured. Pictet 
did this by freezing it and centrifuging away the liquid. Very 
pure chloroform was prepared by Anschutz by taking advantage 
of the interesting fact that salicylide (obtained by treating 
salicylic acid with POCI3 in a neutral solution) forms a crystal- 
line compound with chloroform, giving it up on distillation — 



+ 2CHCI3 :* c,H/ (CHcyj. 





It has been found, however, that pure chloroform is rapidly 
decomposed by aiir and moisture, and this decomposition is best 
hindered by the addition of about 2 per cent, of ethyl alcohol. 
Oil of turpentine, thymol, and other substances may also be 
used for this purpose. 

Its ansBsthetic action appears to be rendered more certain 
by the addition of a small quantity of ethyl chloride. Ethyl 
chloride and ethyl bromide have sometimes been used as an- 
SBSthetics, and a mixture of these substances with chloroform 
has been used, under the name of Sormw/orm, but does not 
possess any special advantage. 

The narcotic action of chloroform is closely connected with 
the amount of chlorine it contains, the entrance of chlorine' 
into the molecule of many aliphatic compounds conferring 
narcotic properties upon the substances so formed. This fact 
is illustrated by the following series of compounds : 

GH4 Methane Without narcotic ef!ect. 

CH3CI Methyl-chloride Weak 

GHjCl^^ Methylene-dichloride Stronger narcotic action. 

CHCl^ Chloroform Strong ,, „ 

GGI4 Carbon-tetra-chloride „ „ „ 



NARCOTICS AND GENERAL ANESTHETICS 51 

In this series the intensity and the persistence^o! the action 
increase with the amount of chlorine. A similar connection 
can he traced in the derivatives of aldehyde, acetaldedyde, 
CHg . CnO, having a slight narcotic action and trichloraldehyde 
(chloral), CCI3 . CHO, a very strong one. 

Although carbon tetrachloride appears to have a stronger 
narcotic action than chloroform, it has no advantage over it, 
but on the contrary seems to be too toxic for safe use. Its use 
by barbers to cleanse the hair has led to accidents, at least one 
fatal case having been recorded. On the other hand, some of 
the other members of this series have been suggested as sub- 
stitutes for chloroform ; methylene dichloride, CHgClg, has been 
recommeiided, as it produces leds vomiting, and methyl-chloro- 
form, CH3 . CGI3, is said to be less dangerous. 

The bromine substitution products of the lower hydro- 
carbons also have narcotic properties. Bromoform, (CHBrg), 
is sedative, and has been used to suppress attacks of whooping- 
cough. Ethyl bromide, (CgHgBr), has also been used for pro- 
ducing short slight anaesthesia ; it is a better anaesthetic and 
is far less toxic than ethylene-dibromide, the halogen esters 
of monacid alcohols being generally better anaesthetics and safer 
than the corresponding esters of diacid alcohols. 

Ethyl chloride is used as a general anaesthetic and also as 
a local one, the latter by spraying it on to the surface to be 
operated upon. Its use in this case has nothing to do with 
the presence of chlorine in the molecule, but is due simply to 
its low boiling-point, the rapid vaporization producing so great 
a cooling as to cause anaesthesia. Ether is often used in the 
same way, and methyl-ethyl ether, CH3 — O — CgH^, which has 
a very low boiling-point, would be very useful for this purpose, 
as also would be the lower paraffins. 

The volatile general anaesthetics are too transient in their 
action to be used as hypnotics for continued action, but never- 
theless, a compound closely related to chloroform has proved 
very useful for the latter purpose. It was known that chloral 
hydrate, (CCl3CH(OH)2), is hydrolyzed by alkalies, giving 
chloroform and alkaline formate, and thinking that a similar 
action might take place in the body, Liebreich suggested its 
use as an hypnotic. It was found to possess strong hypnotic 

4* 



52 SYNTHETIC DRUGS 

properties, but Mering ^ showed that it does not form chloro- 
form in the body, being reduced to trichlorethyl alcohol instead, 

CCI3 . CHO -> CCI3 . CHj . OH. 

It has been suggested that the action of the halogen nar- 
cotics is due to the liberation of free halogen in the body,^ 
but there are several facts not in harmony with this view. 
One of the chief of these is that after administering some 
of these substances, the amount of alkaline chlorides in the 
urine is not increased. For example, after taking chloroform, 
the amount of chloride is increased, but not after taking 
chloral-hydrate, carbon tetrachloride, and dichloracetic ester, 
ClgCH — COOCgHs, all of which have an hypnotic action.* On 
the other hand, trichloracetic acid splits off. chlorine in the 
body, and has no hypnotic action. 

Although chloral hydrate was the first artificial hypnotic 
to come into general use, it suffers itom many drawbacks. 
Thus, it cannot be injected subcutaneously like morphine, and 
it has a harmful by-effect on the heart. These drawbacks 
cannot be got rid of, but attempts have been made to prepare 
derivatives in which the unpleasant taste and burning feeling 
in the stomach produced by chloral-hydrate should be absent. 
All these preparations depend for their Jise upon the regenera- 
tion of chloral itself, as it is found that those which are more 
stable have no hypnotic action, and therefore all of them must 
possess the injurious by-effects of chloral itself. For this 
reason these derivatives of chloral are at a disadvantage com- 
pared with the hypnotics of other classes, and they owe their 
origin rather to the cheapness of chloral and to the fact that 
it was the first synthetic hypnotic to be brought into use. 

Most of these chloral derivatives depend for their produc- 
tion on the reactivity of the aldehyde group in chloral. Conden- 
sation products of chloral with oximes have been prepared, 
but they have not come into practical use. Their formation is 
in accordance with the general equation — ^ 

1 Zeit physiol. Chem,, 6 (1882), 480. 
"Binz, A. e, P. P., 6 (1882), 810. 
5 Kast, Z^t, physiol. Chem., 11 (1887), 280. 
* D. B. P., 66,877. 



NARCOTICS AND GENERAL ANMSTHETICS 53 

H 

/ 

CCL.OHO + X=NOH = COlj— C— OH 



\ 
O— N=X 



Examples are- 



H 

/ 
CCL— C— OH CH3 

\ / 

O— N=C 

\ 
CH, 

from acetoxime, and similar compounds from nitroso-naphthol, 
benzaldoxime, camphor-oxime, etc. Other derivatives include 
those in which the aldehyde group has been combined with 

OH 

basic radicles, e,g, chloral-ammonia, CCI3 — CH — NHg, chloral- 
imide, CClg— CH=NH, etc. 

Chloral-formamide, CCI3— CH— NH— CHO, known as 



OH 

Ghloralamidej is used as a mild hypnotic and sedative. 

Other compounds have been prepared by combining the alde- 
hyde group in different condensations with sugars, but these are 
not now used in medicine. 

Dormiol is a condensation product of chloral with the hyp- 
notic substance, tertiary amyl alcohol — 

CH3 H OH3 

CCI3— CHO + HO— C— CH3 = CCI3— C— 0— C— CH3 

C2H5 OH CgH, 

It is a liquid with a burning taste and is insoluble in water. 
It is as poisonous as chloral, and closely resembles it in its 
action. 

A tasteless solid polymeride of chloral, which possesses strong 
narcotic properties, has been obtained by the action of aluminium 
chloride on chloral. Other tasteless compounds have been 
obtained by combining chloral with orthoform and " new ortho- 



54 SYNTHETIC DRUGS 

form " (see Chapter VII.). Hypnal is formed by the condensa- 
tion of chloral with antipyrine, but this compound, as well as 
many others of the same type, has no advantage over a mixture 
of their components, as they readily split into these, and hence 
act in the same way as the mixture. The only advantage 
which can sometimes be claimed for them is that the unpleasant 
taste of free chloral is masked. 

OH 

/ 

Chloral-urethanCy CCl, — CH , was first 

NH— COOCjjHfi 
prepared to combine the hypnotic action of chloral with that 
of urethane. An ethylated derivative of this is soluble in 
water, and has been given the name of Somnal. 

Butyl-chloral, CClg — CHjj — CHO, has a stronger hypnotic 
action than chloral, but its effect disappears more rapidly, 
and its irritant action on the stomach is stronger than that 
of chloral. Trigemin is a compound of butyl-chloral hydrate 
and pyramidon (see Chapter V.). 

Acetone-chloroform (tertiary-trichlor-butyl alcohol), dis- 
covered by Willgerodt^ in 1886, has been introduced into 
medicine under the name of Chloretone. It is prepared by 
adding potash to a mixture of chloroform and acetone, and 
is a white crystalline solid, melting at 96-97^ C. 

CH3. .OH 
* (CH3),C0 + CHCI3 » ^„><^^, 

CHj'^ ^CClg 

It has a great advantage over chloral in having no irritant 
action on the stomach. On the contrary, it has a sedative 
as well as an anaBsthetic action, and very favourable results 
have attended its use in sea-sickness, vomiting, chorea, etc. It 
is the chief ingredient in the proprietary medicine known as 
** Zotos." It also possesses antiseptic powers, for the sake of 
which it has been occasionally used, and it has sometimes, 
found employment as a local anaesthetic for the mucous 
membrane of the larynx. 

The corresponding bromine compound, CBrj . C(CHg)2 . OH, 
is known as Brometone, and is also used as a sedative. 

^B«r., 19(1886), 2466. 



NARCOTICS AND GENERAL ANESTHETICS 



55 



Bromal hydrate, GBr^ . CH(0H)2, is of no use as an hypnotic, 
hut in large doses it has an ansBsthetic action. The corre- 
sponding iodine compound, CI3 . CH(0H)2, is toxic, and affects 
the muscles and nerve-endings, but has only a slight action on 
the higher centres, and therefore has practically no hypnotic 
action. 

In general, the aromatic halogen compounds have no 
hypnotic action, but tribromosalol (Cordal) appears to be an 
exception, as it is said to be a good hypnotic. 

On the other hand, a large number of aliphatic bromine 
compounds have been brought into use as mild hypnotics and 
nervous sedatives. These are mostly derivatives of urea or 
of borneol or valerianic acid, and probably owe their sedative 
action partly to the presence of the bromine atom, and partly 
to the organic radicle present. They are described and enu- 
merated in Chapter XII. in the section dealing with bromine 
compounds (pp. 187-189). 



Hypnotics, the Action of which is Connected with the 

Presence of Alkyl Geoups. 

In a large number of compounds the presence of an ethyl 
group seems to confer upon the substance the power of enter- 
ing into a close connection with the nervous system. In the 
case of ethyl alcohol, an excessively large dose is required to 
produce sleep, but a number of compounds have been dis- 
covered which have a hypnotic action in much smaller doses, 
although their action appears to be due chiefly to the presence 
of ethyl groups. This difference in their behaviour is probably 
accounted for by the fact that alcohol is largely oxidized by 
the tissues, and so only a small fraction of it can produce an 
hypnotic effect, while these other compounds offer a certain 
amount of resistance to oxidation, and therefore can exert a 
more powerful hypnotic action. 

Methyl alcohol has no narcotic action ; in the other mono- 
hydric fatty alcohols, the narcotic action increases with increas- 
ing length of the unbranched side chain. In general, primary 
alcohols are less active than secondary, and these are less 
active than tertiary. In the case of tertiary alcohols, the 



56 SYNTHETIC DRUGS 

strength of the action depends upon the nature of the radicles 
attached to the tertiary carbon atom. If the radicle is methyl, 
the action is relatively weak, but if it is ethyl it is stronger, 
and the strength increases with the number of ethyl groups. 

Amylene hydrate, HO — C^ , was introduced as a 

hypnotic in 1887, but the alcohols have not been used as 
general inhalation ansesthetics, owing to the slight volatility 
of the higher members, which are the only ones possessing 
marked narcotic properties. On the other hand, the ethers are 
far more volatile, and ordinary ethyl ether, G^^ — ^O — OgHg, is 
the most widely used general anesthetic. 

If one of the hydrogen atoms in urea be replaced by a 
tertiary alkyl group, derivatives are obtained possessing a 
narcotic action. In accordance with the general rule, those 
containing an ethyl group united to the tertiary carbon atoms 
have a greater effect than those which contain only methyl 
groups in this position. For instance, substances containing 

/OH, 

tertiary amyl, — — CHg, or tertiary heptyl, — C(C2H5)3, are 

more active than those containing tertiary butyl, — C(0H3)3. 

/NH-C(CH,), 
Tertiary-butyl-urea, COc^ , produces sleep in 

.NH— C(CH3)2C2H6, 
doses of 4 grams ; tertiary amyl urea, C0<^ 

is an excellent hypnotic, which is both more active and more 
pleasant to take than amylene hydrate. It is, however, slower 
in its action on account of its smaller solubility. This sub- 
stance is completely oxidized in the organism, but symmetrical 

/NH-C(OH,),CA 
di-amyl-urea, 00^ , is a very stable sub- 

\NH-C(CH,)jCjHs 
stance, which passes into the urine unchanged and has no 
physiological action. Tertiary-heptyl-urea is very slightly 
soluble. In doses of 1 gram it produces first intoxication, 
and afterwards sleep. 



NARCOTICS AND GENERAL ANESTHETICS 57 

Besides the urea derivatives already mentioned, many other 
amides possess hypnotic properties, but most of these are un- 
certain in their action. Of greater importance are the ureides 
of dibasic acids (cyclic ureides), many of which have strongly 
marked sedative properties. Thus, diethyl-malonyl-urea — 

C2H5 CO— NH 

C2H5 CO— NH 

and ethyl-propyl-malonyl urea — 

C3H7 CO— NH 

>c< >co 

CgH, CO— NH 

^ave a strong hypnotic action; whilst dipropyl-malonyl-urea 
has so intense an hypnotic action that it is too dangerous to be 
used. 

Special mention must be made of Veronal (diethyl-malonyl- 
urea, also known as diethyl barbituric acid and Barbitone), 
which has attained a very great clinical importance, and is 
now perhaps more widely used than any other synthetic 
hypnotic. It was formerly supposed to be practically free 
from toxic properties, but lately several cases of veronal 
poisoning have occurred. Nevertheless, in the usual doses, 
it is of very low toxicity and free from harmful by-effects, 
and has the advantage, compared with most synthetic hyp- 
notics, in the matter of taste, solubility, and promptness of 
action. Its sodium salt — 

C2H5 CO— N— Na 



^C^ ^CO 

C2H5 CO— NH 



or more likely — 



C2H5 CO— N 

^C/ V_-0— Na 

C2H5 CO— NH 

known as Veronal- Sodium {Medinal)^ has the valuable property 
of being extremely soluble (1 in 6) in water. Veronal, which 



58 SYNTHETIC DRUGS 

is a white crystalline solid, is prepared by a general method 
applicable to other di-alkyl barbituric acids. This consists in 
allowing dialkyl derivatives of malonic ester to react with urea 
or alkyl substituted ureas in presence of sodium ethoxide or 
other metallic ethoxides.^ 

/CO-OC^, HjN. 
EaC/ + >C0 



.CO— NH. HOCaHg 

= RaC/ )C0 + 

^CO— NH/ HOCH 



2-"8 I 



Another method of preparing these compounds is to convert 
the dialkyl malonic acids into chlorides, and then to heat these 
with urea.' 

/CO— CI HgN. .CO-NHv 

RgCC + )C0 = E„C< >C0 + 2HC1 

\C0— CI HjN/ \C0— NH/ 

Instead of using alcoholic sodium ethoxide as a condensing 
agent in the first process, one can employ the metsd sodium 
itself, or its amide or the dry pawdered sodium ethoxide.^ 
The presence of an alkyl group confers hypnotic properties 

on many of the urethanes. Ethyl urethane itself, CO^ , 

^OCjH, 

is a mild hypnotic but methyl-propyl-carbinol-urethane, known 

as Hedonaly has a stronger hypnotic action. It is not much 

used, however. It can be prepared by the action of warm 

methyl-propyl-carbinol on urea nitrate. 

CQ/ + HO— CH 



\ 



NH, . HNO, 



\C,H, 



NH, 



= C0<^ .CH3 + NH^NO, 

O— CH 

\ 
OjHy 

1 E. Fischer, Annalen, 335 (1904), 334 ; Merck, D. B. P., 146,496. 
» D. B. P., 146,949, 'Ibid., 147,278, 147,279, 147,280. 



NARCOTICS AND GENERAL ANESTHETICS sg 

This method can be applied to the preparation of other similar 
compounds, using various secondary alcohols.^ The introduc- 
tion of an acyl group (such as CO — GHj) into the amino group 
of the urethanes lessens their toxicity, but does not otherwise 
alter their physiological action. 

The pinacones show a narcotic action, which is least in the 
case of dimethyl-pinacone — 

CHgv ^CHo 

)C(OH)— 0(OH)< 
greater in the case of methyl-ethyl-pinacone — 

>C(OH)— C(OH)< 
and greatest in the case of diethyl-pinacone — 

>C(OH)— C(OH)C 

Ketones and Sulphones. 

Most of the ketones have hypnotic properties. Acetone is 
somewhat similar in its effect to ethyl alcohol ; diethyl-ketone, 
(C2H5)2 . CO (propion), is a stronger hypnotic and ansBsthetic, 
but its insolubility and unpleasant taste have prevented its 
extended use. Benzophenone, (Cgn5)2CO, has a slight hypnotic 
action, but much less than that of the aliphatic ketones. The 
mixed aromatic and aliphatic ketones have more marked hyp- 
notic properties in virtue of the aliphatic portion of the mole- 
cule, acetophenone (hypnone), C^H^ — CO — CH3, being a fairly 
strong hypnotic, while phenyl-ethyl ketone, CgHg — CO . CgHg, 
has a still more powerful action. 

Of far greater practical importance are the sulphone deriva- 
tives obtained from the ketones by the action of the mercaptans, 
and subsequent oxidation of the condensation product thus 
formed — 

Rv HSK" Rv .SR" + H2O 

>C0 + = ^G( R. .SO2R" 

R''^ HSR" R'/ ^SR" ► yG( 

R'^ \SO2R" 

» D, R. P., 114,396. 



6o SYNTHETIC DRUGS 

Baumann and East discovered that sulphonal — 

CHg SO2 CgHg 

CH3 SO2 — CgHg 
when administered to animals, produced a strong hypnotic 
effect. A large number of sulphones were then examined by 
these investigators, who found ^ that di-sulphones in which the 
sulphone groups are united to two different carbon atoms, are 
inert ; for example, ethylene-diethyl sulphone — 

CH2 — SOg — CgHg 

CHg — SO2 — C2H5 
They also found that sulphones derived from methane {i,e. 
those in which the two SO2 groups are united to a CH2 group) 
are inert, as also are those containing methyl groups but no 
ethyl groups. 

ySOg — CH3 

E,g. Methylene - dimethyl - sulphone, GH^c^ , is 



SO2— CH, 



inactive. 



,S02 — CgHg 



Methylene-diethyl-sulphone, CH2<^ , is inactive. 

ySOg CHg 

Ethylidene - dimethyl - sulphone, CH3 — CH<^ , is 

^SOg— CH3 

inactive. 
On the other hand, ethylidene-<i*et^2/Z-sulphone — 

CH3— CH(S02 . C2H5)2 
has a similar action to that of sulphonal, while the entrance 
of an ethyl group into the central methylene group also brings 
about the appearance of a narcotic action. 
E,g. C2H5 — CH(S02 . CH3)2, slight narcotic action. 
(C2H5)(CH3)C(S02CH3)2 „ „ ,, 

^2^6 \ yS02 — CH3 

}G^ , isomeric with, and similar physio- 

C2H/ \sO2-CH3 

logical action to, sulphonal (" reversed " sulphonal). 



1 



ZeU. physiol Chem., U (1890), 52. 



NARCOTICS AND GENERAL ANESTHETICS 6i 

CgHftv .SO2— CjjHg 

Trtonalf jG^^ , has a more powerful and 

GS/ \sO2-CA 

prolonged action than sulphonal. Tetronal, (C2H5)2C(S02C2H5)2, 
is very insoluble, and therefore is not so good an hypnotic, but 
for dogs it appears to have the most powerful action of all the 
sulphones. 

The above examples indicate that the intensity of the hyp- 
notic action appears to be conditioned by the number of ethyl 
groups in the molecule. A study of the fate of these compounds 
in the body has revealed the curious fact that those sulphones 
which are readily decomposed by ordinary chemical means are 
relatively stable in the organism, while those which are more 
resistant to ordinary chemical reagents are oxidized by the 
organism. For example, sulphonal, " reversed " sulphonal, 
trional and tetronal, though very stable to strong reagents, 
such as permanganate, are to a great extent decomposed in the 
organism, while CH2(S02 . C2H5)2, which is easily decomposed 
by alcoholic potash, is found unaltered in the urine. 

SiBiphonal and trional are of great practical importance, as 
they are amongst the most widely used hypnotics. Technically, 
sulphonal is prepared by the condensation of ethyl mercaptan 
and acetone in the presence of zinc chloride, and oxidation of 
the mercaptol thus formed with excess of permanganate.^ 

CH3. HSCgHg CHgv .S — C2H5 

CH3/ HSC2H5 Gk/ \s— C2H5 

CHgv ySOg — C2H5 

GB./ \S02— C2H5 

Trional is prepared in a similar manner, but the preparation 
is complicated by the necessity of introducing the extra ethyl 
group in place of methyl. This can be done in three different 
ways.^ 

(1) Methyl-ethyl-ketone is condensed with ethyl mercaptan 
by means of dry HCl, and the resultant mercaptol oxidized. 

^ Baumann, Ber., 19 (1886), 2808. 

2D. R. P., 49,073, 49,366; Fromm, Annalen, 253 (1889), 148. 



62 SYNTHETIC DRUGS 

*\co — --* ^g{ 

This method is strictly analogous to the method of preparing 
sulphonal. 

(2) Propionic aldehyde is condensed with ethyl mercaptan, 
and the product oxidized as before. The oxidation product is 
then methylated with methyl iodide and caustic soda to form 
trional. 

^2H^6\ HSCgHg C2H5V .SCgHg 

\C=0 ► >C< 

H/ H8C2H5 H^ \SC2H5 

H-^ \sO2C2H5 Cn/ \S02— C2H5 

(3) By starting with ordinary aldehyde, instead of propionic 
aldehyde, and ethylating with ethyliodide and sodium ethylate 
in the last stage instead of methylating, trional can be obtained, 

CH-v CHov /SCoHr, CH.-V •SOg CgMe 

an/' \sOj— C2H5 



CHAPTEE V. 

ANTIPYBETICS AND ANALGESICS. 

(Debivatives of Aniline and Phenylhydbazine.) 

The substances to be dealt with in this chapter include some 
of the most important of the synthetic drugs. These substances 
were originally introduced on account of their power of reduc- 
ing the body temperature in fever (antipyretic action), but 
their present importance is due, to an even greater extent, to 
their action on the nervous system in soothing pain (analgesic 
action). 

The original idea of chemists was to produce a compound 
with properties similar to those of quinine, and this they sought 
to accomplish by preparing substances the composition of which 
was closely related to that attributed to that compound. The 
formula in vogue for quinine was however incorrect, but in 
spite of this, several compounds were produced which had a 
marked antipyretic effect, but which lacked one very important 
attribute of quinine, namely, its specific effect against malaria. 
Quinine was shown to be a derivative of quinoline, and further 
to differ from the less active cinchonine in containing a methoxy 
group in the epi (1-6) position to the quinoline nitrogen, 

^ I J I Quinoline itself has an antipyretic action, but 

cannot be used as a drug, owing to its unpleasant by-effects. 
Paramethoxyquinoline has a weaker antipyretic action than 
quinoline, but in accordance with the previously mentioned fact 
that tetrahydroquinoline has a stronger physiological action than 
quinoline, it was supposed that quinine was a derivative of epi- 
methoxy-tetrahydroquinoline. This supposition is now known 
to be incorrect, but nevertheless when 6-methoxyquinoline, 

63 



64 SYNTHETIC DRUOS 



CHjO 




, is reduced to its tetra-bydro compound. 






^B 



, we obtain a substance {Thalline) with a 



[H 

strong antipyretic action, though without any specific efifect in 
malaria. It is not used as a drug, as it has harmful effects on 
the blood and kidneys. 

Some earher experiments had been carried out on N.-alkyl 
quinoline derivatives, and it was found that the introduction 
of an hydroxyl group caused the effect to appear more rapidly, 
but also to cease more quickly and suddenly. For example, 

CHg 

kg^irine, hydroxy N. -ethyl- tetrahydroquinoline, 



"■yj 

HO N 



OH. " 



'2 



2^6 

more rapid than KairoUne A or Kairoline B, which are re- 
spectively N.-ethyl-tetrahydro- and N.-methyl-tetrahydro-quino- 
lines — 

N N 



i 



2^6 CHg 

These substances are all useless, owing to their toxic action on 
the red blood-corpuscles. 

Although the artificial quinoline derivatives have proved use- 
less in medicine, a compound produced by Knorr,^ with the 
intention of obtaining a substance resembling quinine, met with 
a great and surprising success. The compound in question 
was first considered by Enorr to possess a structure ^ similar 
to that which was then attributed to quinine. Later Knorr, 
however, showed that it was more closely related to pyrazole 

» Annalen, 238 (1887), 137. ^ ^er., 17 (1884), 2037. 



ANTIPYRETICS AND ANALGESICS 



65 



HN 
/\ 

N CH 

II II 
HC CH 

in structure, being in fact phenyl-dimethylpyrazolone — 

N-C^j 
CH,— N/\00 



CHq C 



CH 



This compound has attained a very extended use in medicine 
under the name of antipyrine. 

It is obtained by the action of aceto-acetic ester on phenyl- 
hydrazine, whereby a hydrazone is formed, which on heating 
loses the elements of alcohol, with the formation of phenyl- 
methyl-pyrazolone. This is then heated with methyl iodide 
and methyl alcohol at 100-150'' C, which transforms it into 
antipyrine.1 



Phenylhydrasine. 



/ 



NH— CjHs 



HN 



CH 






HN 



/ 



N 



0— CjH, 



lo 



,<! 



H 



0^5 



a^^^ 



H 



CHj— O; 



io 



Aceto-acetic ester. 



N-CeH, 



/\ 



CH3— N CO 

CH3— C=rCH 



Hydrazone. 

\ Heating. 

N- 

/\ 
HN CO 



■^6^5 



GH3 C :— -— . CH 

Phenyl.methyl-pyrazolone. 



Phenyl-dimethyl-pyrazolone. 

This view of its constitution is confirmed by its direct syn- 
thesis from CgHg — NH — NH — ^CHg and aceto-acetic ester. 



ID. R. P., 26,429, 33,536, 40.337, 42,726. 



66 SYNTHETIC DRVQS 

Its salt with acetylsalioylio acid (c/. p. 157) is known as 
Acetopyrine. 

Antipyrine has a very strong antipyretic action, which is 
far greater than that of quinine, and it is free from injurious 
efifeot on the hssmoglobin, but it has no specific action against 
malaria. On the other hand, it has the very useful property 
of diminishing neuralgic pains (analgesic action), which has 
secured for it a great popularity. A large number of deriva- 
tives of antipyrine have been placed on the market, but most of 
these have no advantage over it, and many of them are very 
loose compounds of antipyrine and other substances, which 
act practically like mixtures. One derivative of antipyrine has, 
however, proved of great value, namely, 4-dimethyl-amino- 
antipyrine. This substance, which is called J£yramidgx^ or 
Amidopyrine, is about three times as powerful in its action as 
antipyrine, and also has the advantage of being free from in- 
jurious effects on the heart (Kobert). It is prepared by treating 
an acid solution of antipyrine with sodium nitrite, whereby 
nitroso-antipyrine is formed. This on reduction gives amino- 
antipyrine — 



CH3— N/\CO CH3— N/\CO 



a-N/XCO 

[3— cLJo— 



CH.— cLJo— NO "* CH,— ci=lc— NR 



which is isolated in the form of its benzylidene derivative {i.e. 
condensation product with benzaldehyde) — 

CH3— N/XGO 

CH3— cL=IC— N =CH— CeHfi. 

This is then decomposed with hydrochloric acid, and on methy- 
lation yields pyramidon — 

N^ 
CH3-N/\C0 

CH3— cL='C— N(CH3)j. 

The success of antipyrine, and the mistaken idea that its 
action might belong to phenylhydrazine derivatives in general, 



ANTIPYRETICS AND ANALGESICS 67 

led to the production of a large number of these, most of which 
are, however, without therapeutic value. The intense toxic 
action of phenylhydrazine is weakened by the entrance of 
acetyl groups, but the monoacetyl derivative {hydracetin), 
CeHg— NH— NH . CO . CH,, and the diacetyl derivative, 
C^HgNH — N(GO . CH,)2, are both too toxic to be of any use. 
Other phenylhydrazine derivatives have been prepared, in 
which the carboxyl group enters the molecule, e.g. the hydra- 
zone of IsBvulinic acid — 

CHg 

C=N— NH— CeHg 

COOH 

HOOC/NNH— NHj, 
called Antithermin, but this, like Orthtiif I I 

and other* derivatives of this type, is too toxic for use. 

More success has attended a compound in which acid amide 
groups are introduced into the molecule, meta-benzaminsemi- 
carbazide, 

HjjN— CO— /V-NH— NH— CO— NH„ 

having been extensively used as an antipyretic under the name 
of Cryogenin, 

Maretin is meta-tolylsemicarbazide, 

CH3— /y-NH— NH— CO— NHj. 

Anilinb Dbbivativbs. 

The antipyretics already described owe their origin to the 
endeavour to prepare substances similar to quinine. Those to 
be dealt with in the present section are based on the discovery 
of Cahn and Hepp,^ that aniline and acetanilide have powerful 

> ZentralMaU f, him. Med,, 33 (1866) ; Bar. hUn. W. (1887), 1 and 2. 

5* 



68 SYNTHETIC DRUGS 

antipyretic and anti-neuralgio properties, and. the low price of 
aniline gave a atill further stimulus to the endeavour to find a 
suitable derivative of it that could rival the more expensive 
quinine and antipyrine. Aniline and its salts have a strong 
antipyretic action, but they are readily absorbed, and owing to 
their action on the hsBmoglobin, give rise to toxic, symptoms. 

By the entrance of an acetyl group, aniline is rendered more 
resistant and less toxic, so that acetanilide, C^Hg . NH . CO . CH,, 
has been used in medicine under the name of ^* antifehrinJ* 
It has marked antipyretic properties, an^ also acts as an 
analgesic. Though far less toxic than aniline, yet its physio- 
logical effect is due to the Blow liberation of aniline, and after 
a time symptoms of aniline poisoning may become apparent. 
It is only used now on account of its cheapness — it is by far 
the cheapest of all antipyretics — and it forms the active in- 
gredient of many of the secret remedies that are advertised for 
the cure of headaches, etc., and is also used to adulterate other 
m<Mre expensive drugs, such as phenacetin. Small quantities 
of acetanilide are oxidized in the body to para-aminophenol,^ 
and the observation of this fact has led to the introduction of 
various derivatives of para-aminophenol as antipyretics. Be- 
fore passing on to these, attention may be given to some other 
compounds which are more closely akin to acetanilide. In 
most of these cases the compounds that have been introduced 
could have no marked advantage over acetanilide, as they like- 
wise depend on the liberation of free aniline for their physio- 
logical effect. For example, benzanilide and salicyl-anUide 
resemble acetanilide, but have to be given in bigger doses, as 
they are less readily split up in the intestine; while on the 
other hand, formanilide, owing to the ease with which it under- 
goes hydrolysis, is far more toxic than acetanilide. Toluidine 
derivatives also have not the slightest advantage over acetaniUde, 
as all the three toluidines have, when once in the system, prac- 
tically the same toxic action as aniline. 

Attempts have been made to obtain more soluble derivatives 
of acetanilide by the introduction of acidic groups. As the 
sparing solubility of acetanilide does not have any injurious 
effect on its therapeutic action, these attempts must be regarded 

iSchmiedeberg, A. e, P. P., 8 (1878), 1. 



ANTIPYRETICS AND ANALGESICS 69 

as quite unscientific, especially as the resulting compounds are, 
as was to be expected with acidic substances, quite inert and 
without the characteristic action of acetanilide. An example 

NH . CO . CH3 

of this class is Cosaprin,^ | 1 

SO3H 

Substances containing a sulphonic acid group in the a> posi- 
tion of the acetanilide molecule are said to be an exception to 
the rule that acidic substances are inert. These derivatives are 
said to be easily soluble and to have an antipyretic action, but 
they do not appear to have come into use, and it may therefore 
be that the original statements as to their antipyretic action 
were mistaken. 

CgHg . NH . GO . GH2 . SOgNa is an example, and is prepared 
as follows : The aniline salt of chloracetic acid is treated with 
phosphorus pentoxide — 

W^5— iN --_g ^ CeHfi . HN . CO . CHaCl. 

\0— CO— CHjCl 

The product is then heated with an aqueous solution of sodium 
sulphite — 

CgHg . NH . CO . CHgCl + NagSOg 

= NaCl -K CfiHs . NH . CO . CHg . SOgNa, 

the sodium salt of the acetanilide sulphonic acid separating on 
cooling.^ 

Methyl-acetanilide, C^Hg . N(Cn3) . CO . CHj, exalgirif has 
toxic properties and is not much used in medicine. 

An aniline derivative of a different type is phenyl-urethane, 
Etiphorin, C^Hg . NH . COOCjHg. It is prepared by the action 
of aniline on chloro-formic ester — 

CgHfi . NH2 + CI . COOC2H5 = CgHg . NH . COOC2H5 +' HCl. 

It is far less toxic than aniline, and has marked analgesic pro- 
perties, but is irregular in its antipyretic effect. 

' D. R. P., 92,796. ' Ibid., 79,714, 84,664. 



70 SYNTHETIC DRUGS 

Dbbivatives of Paba-aminofhbnol. 

The use of para-aminophenol deriyatiyes as antipyretics is 
due to the discovery that aniline and its simple derivatives are 
partially converted by the organism into para-aminophenol,^ 
which is then eliminated as a sulphonic acid derivative or as 
a compound of glycuronic acid. Para-aminophenol is far less 
toxic than aniline, but it still has an action on the hsBmoglobin 
sufficient to be harmful in moderate doses. The replacement 
of the hydrogen of the amino group by an acetyl group, with 

the formation of HO< C ^ NH . GO . CH,, yields a compound 
with a lower toxicity than para-aminophenol, and with anti- 
pyretic and anti-neuralgic properties, but still not quite satis- 
factory as a drug. The next step was the replacement of the 
hydroxylic hydrogen by radicles, and diacetyl-aminophenol, 

CH3 

CHj . CO . ^ ^ NH . CO, was prepared, but it was found 
to be inferior in its action to para-ethoxy-acetanilide and 

para-methoxy-aoetanilide, GJ3,^0 ^ ^ NH . CO . CH„ and 

CHgO \ y >NH . CO . CHj, which were named phenacetin and 
methckcetin respectively. 

The last-named compound was found to possess antipyretic 
and anti-ileuralgic properties in the highest degree of all, but 
phenacetin, in which these properties are only slightly less 
well marked, has the advantage of having less toxic action on 
the blood. Phenacetifif which was the first drug of this class' 
to be placed on the market, has retained the lead ever since, 
and is by far the most important compound of this class, and 
indeed, at the present time, is probably more used than any of 
the other antipyretic and analgesic substances. 

The starting point for the synthesis of phenacetin is para- 
nitro-phenol. The sodium salt of this is treated with ethyl 
bromide, and the product reduced with tin and hydrochloric acid. 
The para-phenetidine thus formed is then acetylated by boiling 
with glacial acetic acid.^ 

^ Schmiedeberg, loc, cit^ 

a Paul, ZHt agwd, Chem. (1896), 694 ; Hinsberg, AnncOen, 305 (1899), 
278; Hurst and Thorpe, /. O. S., 107 (1915), 184. 



ANTIPYRETICS AND ANALGESICS 



71 




NO. 



0C2H, 



NH, 




NH . CO . CH, 



C2H5 




C2H5 



Para-phenetldine. Acetyl para-phenetidine 

(phenacetin). 

On the oommercial scale, an ingenious variation of this pro- 
cess has been devised, whereby one molecule of para-nitrophenol 
is made to furnish a large number of molecules of phenacetin. 
This process is adopted on account of the fact that para-nitro- 
phenol is rather difSicult to obtain in the pure condition. In 
this process, the para-nitrophenol is converted into para-phene- 
tidine by the method already described, and the phenetidine 
is then diazotized and coupled with phenol in the presence of 
sodium carbonate. This is then ethylated, and the product 



OC2H5 



NgCl 



OH 



\y 



OC2H5 OH 





+ HC1 



i 



"0^0 




Na 



CjH^O 



OCoH 





2-"6 



thus obtained is then reduced, whereby two molecules of phene- 
tidine are obtained. These can then be converted into phena- 
cetin by acetylation, or can be made to yield a double quantity 
of phenetidine by repeating the above-described process^ of 
diazotization and coupling with phenol. 

Phenacetin is also obtained by the ethylation of ^-acetylamino 
phenol.^ 

Phenacetin is only slightly toxic, but when given in very large 
doses, some methsemoglobin is found in the blood. Its anti- 
pyretic action is due to increased heat-loss from the surface of 
the body, but this drug is used chiefly for its analgesic action, 
in the treatment of headache, neuralgia, etc. 



1 D. R. P., 48,643. 



^Ibid,, 85,988 ; Hinsberg, loc. cit. 



72 SYNTHETIC DRUGS 

Several other derivatives of the phenacetin group have been 
prepared, but none of them have any novel therapeutic action, 
as in all of them this depends on the liberation of para-amino- 
phenol or para-phenetidine in the body. Indeed, it has been 
shown by Treupel and Hinsberg,^ that the antipyretic action 
of aniline and para-amino-phenol derivatives is, within certain 
limits, proportional to the amount of aniline, para-amino-phenol 
or phenetidine, formed in the organism. This statement is 
based on the fact that, in those cases where an antipyretic 
action is found, the urine shows the indophenol reaction, and 
that the intensity of the reaction is roughly proportional to the 
strength of the antipyretic effect. This reaction is carried out 
as follows: The urine is acidified with two drops of hydro- 
chloric acid, and two drops of a one-per-cent. solution of sodium 
nitrite added, whereby the phenetidine (or other primary amine) 
is diazotized. On adding ah alkaline solution of fi naphthol, a 
red coloration is produced, which becomes violet on acidifying 
with hydrochloric acid. This reaction is given by — 

OCHg OC2H5 OC3H7 





.aQ 



and 

H . CO . CH3 NH . CO . CH3 NH . CO . CH3 

which resemble phenacetin in their physiological action, but not 

— ^ /CgHfi 
by H0< /^\ ' » which has no antipyretic action, and 

\C0 . CH3 

no action on the blood. If, however, the hydrogen of the amino 
group is substituted in phenacetin itself, physiologically active 
substances are obtained. For example, the methyl derivative, 

CaHfiO< C ^ N . CO . CHj, has greater narcotic and anti-neuralgic 

CH, 
properties, but less antipyretic action than phenacetin, while in 
the ethyl derivative, C2H5O . C^H^ — N — CO . CH3, there is an 

C2H5 
increase in the narcotic power, accompanied by a decrease in 
the toxic properties, the antipyretic action being retained with 

1 A. e. P. P., 33 (1894), 216. 



ANTIPYRETICS AND ANALGESICS 



73 



slightly diminished intensity. In the higher members of the 
series, such as the propyl and butyl derivatives, the narcotic and 
anti-neuralgic properties rapidly diminish with the increase in 
the molecular weight. In this series the maximum antipyretic 
and anti-neuralgic effect is shown by the methyl and ethyl de- 
rivatives, and the minimum toxicity by the ethyl compound. 
This corresponds to the effect of substituting the hydroxylic 
hydrogen of amino-phenol by alkyl groups, which is illustrated 
by the following table, showing the alteration of the physiological 
effect produced by the entrance of alkyl groups in the hydroxyl 
of acetyl-amino-phenol : — 



Formula and Name of Substance. 



0.H, 



yrO-CS-t 



(1) 



\ 



Methaoetiii. 



NH . 00 . OH, (4) 



C3.H, 






O— 0,H, 



(1) 



Physiological Effect Compared to that 
of p. -acetyl-amino-phenol. 



Anti-pyretic and anti-neuralgic 

effect strengthened. 
Less blood toxicity. 



Phenacetin. 



NH . CO . CHj (4) 



0«H, 



\ 



(1) 



NH . 00 . OHg (4) 



0«H, 



/OCA 



(1) 



\ 



NH . CO . OH, (4) 



Anti-pyretic action maintained, 

analgesic action strengthened. 
Much less blood toxicity. 



Anti-pyretic action slightly weak- 
ened. 

Blood toxicity diminished, but 
toxicity greater than with meth- 
acetln and phenacetin. 



Anti-pyretic action weakened. 



This table shows the superiority of phenacetin over the other 
members of the homologous series. The only substance as yet 
mentioned which appears to have any possible advantage oyer 
phenacetin is its substituted ethyl derivative — 

C2H50<]3N— CO . CH3 



C2H5 

In this case, its possible slight advantages are probably out- 
weighed by its increased cost. 



;Bi 



1 \ 



74 SYNTHETIC DRUGS 

Owing to the slight solubility of phenftcetin, many attempts | ^ 

have been made to prepare more isoluble derivatives, which 
should nevertheless be sufficiently stable to resist the action 
of the dilute hydrochloric acid of the gastric contents, and so 
prevent the liberation of poisonous phenetidine salts. As the 
slight solubility of phenacetin does not appear to interfere 
with its physiological effect, these efforts are not of great 
practical value. The introduction of sulphonic acid or carboxyl 
groups in order to obtain increased solubility, was not likely 
to meet with much success, as generally the presence of acid 
groups tends to destroy the physiological activity of a com- 
pound. For example, both the sulphonic and the carboxylic 
acid of phenacetin are almost inert, but the sodium salt of 
the former has been introduced under the name of Phesin, 

CaHft( X ^ NH . CO . OH3, and is said to have slight temporary 
^SO,Na 

antipyretic properties. 

Similar compounds to phenacetin have been prepared in 
which the hydrogen of the amino group is replaced by acid 
radicles other than acetyl. Para-propionyl-phenetidine (Tri- 
phenin) is similar to phenacetin, but less soluble and hence 
less physiologically active. 

Lactyl-phenetidine (Lactophenin)-^ 

C2H,0<^NH— 00— OH— CH3 

OH 

is more soluble than phenacetin, and has less anti-pyretic action, 
but has well-marked anti-neuralgic and narcotic properties. It 
is mcnre liable to liberate toxic phenetidine hydrochloride. 
Para-ethoxy-pbenyl-succinimide (Pyrantin) — 

CO— CHj, 

C2H50<CI>N 

CO— CH2 

and diacetyl-phenetidine, CqHrO ^ ^ N(COCHa)a, have been 
prepared, but have no value. 



ANTIPYRETICS AND ANALGESICS 



75 



Salioyl-phenetidine is stable, insoluble, and practically inert, 
as would be expected, and amygdophenine — 

H 

I 



CjHsOCZV-NH— CO— C— CeHj 

Ah 

is also rather insoluble and inert. It is the mandelic acid deri- 
vative of phenetidine. 

It has been noticed that phenyl - urethane, Eufhorin, 

. CO . OC2H5, is partially oxidized by the organism 




into para-hydroxy-phenol-urethane, and some of its derivatives 
have been prepared for pharmaceutical purposes. 



/OH 

\00 . CH3 


Acetyl p.-hydroxyphe- 

nyl-urethane 

(neiiTodin). 


Very insoluble in cold 
water. Bapid but 
uncertain anti-pyretic 
action. 


\NH— OOOOjHb 


Para-ethozy-phenyl- 
urethane. 


More certain anti-pyretic 
action. 



The acetyl derivative of the last-named above has been intro- 
duced under the name *' Thermodin" It has a gradual anti- 
pyretic action, is not toxic, and has no depressant action on 
the heart or respiration. It is insoluble except in acid media. 
Various derivatives of this type have been prepared by Merck,^ 
by passing carbonyl chloride into a solution of para-oxyphenyl- 
urethane, or acid derivatives of para-phenetidine in presence of 
alkalies — 



2C,H, 



/ 



OH 



(1) 



+ COCl, 



\nH . COB (4) 

.0— C^.— NH . COR 
= C0< + 2HC1 

^0— CgH^— NH . COB 

where E = CH,, C,Hj, CgHj, OCjHj, or OCjHj. 

If the reaction is carried out in alcoholic solution in presence 
of sodium ethoxide, mixed carbonates are formed — 

ID. B. P., 69,328, 86,803. 



76 SYNTHETIC DRUGS 

.0(H CI) . CO . (CI + H)OC2H5 

CfiH^v + 

\NH . CO . R 

.0— C2H5 + 2HC1 

= C0< 

^O— CgH^— NH . COB 

By varying the alcohol, methyl or propyl groups can replace 
the ethyl group. 

Among other derivatives of phenetidine which have been 
prepared are certain condensation products with aldehydes. 
Mention may be made of Malakin — 




prepared by condensing phenetidine with salicylic aldehyde,^ 
MaXarin? the citrate of methyl - benzylidene - phenetidine, 

C2HO < >N=C— C^H^— CHa, vanillin-phenetidine »— 

.ON 

^N=CH< >0H 

(said to be a good styptic) and the para-phenetidine derivative 
of vanillin ethyl carbonate * — 

OCH3 
C2H50<CI>-N=CH<;30— COOC2H5, 

which has been named Eupyrin. None of these are, however, 
of any particular value. 

A soluble derivative of phenacetin has been prepared by 
Schmidt and Majert, by the action of ammonia on bromacetyl- 
phenetidine (bromo-phenacetin) — 

CAO<CI>NH . CO . CHaBr + H . NHg 

= C2H^0< >NH . CO . CHg . NH2 + HBr. 

The amino-phenacetin thus formed is named PhenocolL Its 

hydrochloride is readily soluble in water, and has a similar 

1 D. R. P., 79.814, 79,857. ^Ibid., 87.897, 98.840. 

> Ibid., 96.342. « Ibid., 101.684. 



ANTIPYRETICS AND ANALGESICS 77 

action to phenacetin, but the action appears and disappears 
more rapidly. It is said to have a greater analgesic action, and 
also to have antiseptic properties, and to be a good substitute 
for salicylic acid as an anti-pyretic in rheumatic fever. Its 
only insoluble salt is the salicylate, SalocolL 

So far, mention has only been made of phenetidine derivatives 
in which the hydrogen of the hydroxyl group has been replaced 
by simple alkyl groups, but several derivatives have been pre- 
pared where this hydrogen has been replaced by more complex 
groups. 

For example, acetylamino-phenyl benzoate — 

CeHg . CO . 0<^NH . CO . CHg, 
acetylamino-phenol acetamide — 

NH2 . CO . CH2 . 0<~>NH . CO . CH3, 
acetyl-ethylamino-phenol acetate — 

C2H5 

CH, . CO . 0<CI>-N— GO . CHg, 
and lactyl-amino-phenyl ethyl carbonate — 

c2h.o . co— 0<c~>nh— co . ch— ch, 

Ah 

have been prepared and described, but do not appear to have 
had any practical application. 



CHAPTEB VI. 

ALKALOIDS. 

A DisoussiON of the chemistry of the alkaloids would be out of 
place in this work, and the reader who desires further informa- 
tion on this head is referred to special works dealing with the 
subject, such as Pictet's " Vegetable Alkaloids." Nevertheless, 
it is of interest to mention some of the recent work that has 
been carried out in this field, a good deal of which has not yet 
found its way into the text-books ; much of this is to be found 
in the section dealing with the isoquinoline alkaloids. 

No precise and satisfactory definition of the term " alkaloid " 
can be giyen, and it has generally been used to denote nitro- 
genous basic substances of a cyclic structure found in plants, 
but it seems advisable to restrict its use to substances possess- 
ing a more or less marked physiological action. The alkaloids 
possess a special interest for the study of the relation between 
physiological action and chemical constitution, owing to the fact 
that many of them, even in small doses, produce very marked 
and definite physiological effects, and that a slight alteration 
in the chemical structure of the molecule often produces a 
decided change in this effect. 

Mention has previously been made of the fact that the re- 
duction of a nitrogenous ring generally produces a marked in- 
crease in the toxicity and strength of the action of the drug, 
and sometimes completely alters its character. For example, 
pyridine has no marked toxic action and lowers blood-pressure, 
but piperidine is very toxic and raises blood-pressure. ^- 
naphthylamine is not very poisonous, and contracts the pupil 
of the eye, but tetrahydro-)9-naphthylamine is more poisonous 
and dilates the pupil. Many other examples of this type will 
be encountered from time to time. In all cases it is probably 
connected with the fact that reduction causes the substance 

78 



ALKALOIDS 79 

more nearly to approach the aliphatic bodies in its properties, 
while in the case of pyridine and qninoline rings, it is connected 
with the change from tertiary nitrogen to the more reactive 
secondary form. 

Although the substances containing reduced rings are more 
active physiologically than those containing pyridine or quino- 
line rings, yet the activity is often apparently dependent upon 
the cyclic structure, as the open chain compounds are in 
general much less active than the corresponding alicyclic ones, 
and nearly all the active alkaloids are possessed of a cyclic 
structure. For example, 8-amino- valerianic acid and y-amino- 
butyric acid are without any particular physiological action, 
but their anhydrides, the cyclic bases piperidon< 



1-2 



NH 



and a-pyrrolidone- 



HiiC CO 



NH 

have a powerful action.^ In the same way pentamethylene 
diamine, NH8[CH2]5Nn2, is not toxic, while piperidine is. 

The size and position of the side chains attached to the ring 
have an important effect, and in some cases relationships have 
been traced between these factors and the physiological action. 
Thus, most of the alkaloids are derivatives either of pyridine 
itself, or of quinoline or isoquinoline, both of which latter con- 
tain a conjugated pyridine nucleus. Pyridine has only a slight 
physiological action, but more active bodies are generally ob- 
tained by reduction or by the entrance of aliphatic side chains. 
The introduction of the latter is accompanied by the appear- 
ance of intoxicating action, which increases with the length 
and the number of the side chains.^ The toxic action of piperi- 
dine itself is not very strong, but it is increased in a-methyl 

1 Schotten, Bar., 21 (1888), 2343; Gabriel, Bar., 28 (1890), 1772, 8885. 
■Kendriok and Dewar, Proc, Roy. Soc., 22 (1874), 482. 



8o SYNTHETIC DRUGS 

piperidine (pipecoline), and still more in a-ethyl piperidine and 
a-propyl piperidine (coniine). The toxicity of these substances 

CH2 

CH3— CH2— CH2— CHvjCHa 

NH 
is in the ratio of 1 : 2 : 4 : 8. 

In a previous chapter reference has been made to the re- 
markable discovery of Grum Brown and Eraser on the effect 
of transforming a tertiary base into a quaternary ammonium 
compound. In the case of almost every alkaloid which is a 
tertiary base, the original action disappears and is replaced by 
a curare-like action. The quaternary methyl and ethyl deri- 
vatives of atropine are partially exceptional; they resemble 
atropine itself in their action on the sympathetic nervous 
system, but differ from it in their action on the central nervous 
system and in having a curare-like action. Thus, atropine- 
methyl-nitrate retains the mydriatic action of atropine, while 
the action of atropine on the brain is lacking in this substance 
and also in the alkyl bromides of atropine and the allied 
alkaloids, hyoscyamine, homatropine, and scopolamine. 

The effect of the presence of hydroxyl groups, carboxyl 
groups, unsaturated linkages, etc., has already been dealt 
with in a previous chapter, and the special importance of the 
esterification of hydroxyl groups by acid radicles in alkaloids 
will be discussed in connection with cocaine, heroin, etc. 

Of the alkaloids which are used in medicine, caffeine, theo- 
bromine, and the other purine derivatives are often considered 
separately, on account of their close relationship to various 
non-alkaloidal substances, such as uric acid, xanthine, etc. 
These alkaloids and their derivatives will therefore be con- 
sidered in another chapter. The morphine group, the isoquino- 
line derivatives, and the derivatives of tropine will be considered 
in the following sections, and there remain quinine, pilocarpine, 
and strychnine as being important from the medicinal point of 
view. Nicotine and many other alkaloids are also of great 
interest, but they are not much used in medicine, and compara- 
tively little work has been done on them during recent years. 



ALKALOIDS 8i 

It has been shown by the work of Jowett ^ and of Pinner ^ 
that pilocarpine probably has the constitution represented by 
the formula — 

C2H5— CH— CH— CHj— C N— CH3 



OH C] 



CO OH2 OH OH 

\/ \^ 

N 

and that isopilocarpine is probably a stereo-isomeride. This 
alkaloid has not yet been synthesized, nor have synthetic sub- 
stances of similar constitution and physiological action been 
introduced into medicine, and therefore it need not be con- 
sidered at length. Pilocarpine illustrates the difficulty often 
encountered in correlating chemical constitution and physio- 
logical action. Pharmacologically, it is very similar in many 
respects to muscarine (hydroxycholine, (HO)202H8N(CH3)3OH), 
to which it bears no particular chemical relationship. On the 
other hand, it may be pointed out that pilocarpine resembles 
nicotine in some of its physiological effects, and that both sub- 
stances contain a iive-membered ring containing nitrogen. It 
is true that nicotine also contains a six-membered nitrogen 
ring, but its physiological action is probably due more to the 
five-membered pyrrolidine ring. (0/. quinine.) 

Our knowledge of the constitution of strychnine is not in pro- 
portion to its importance in medicine ; in fact, until recently no 
constitutional formula had been proposed for it, but lately 
Perkin and Eobinson' have tentatively suggested that the 
structure of this substance may be represented by the for- 
mula on next page. 

With regard to quinine, our knowledge is more satisfactory, 
and although its synthesis has not yet been accomplished, a 
great deal of synthetic work has been carried out in connection 
with it, and therefore a more extended account of this alkaloid 
will not be out of place. 

W. C. iS., 77 (1900), 478, 851; 79 (1901), 580, 1381; 83 (1903), 488, 
464 ; Proc. Chm- Soc., 21, 172. 

*£«r., 33 (1900), 1424, 2357; 34 (1901), 727; 35 (1902), 192, 2441. 
•/.O. iS.,97(1910), 806. 

6 



82 



SYNTBETIC DRUGS 



OHj CH 

CH CH 



CH CHj 
N C CH CH, 



CO N— C 



CH, 



Strychnine. 



H CHj 



A 



H 



The therapeutic value of quinine arises chiefly from the 
fact that it appears to have a specific action in malaria, probaUy 
being far more poisonous to the protozoal parasites than to the 
cells of the host. It has also been widely used as a febrifuge, 
but this is referred to in the chapter on anti-pyretics, and at 
present it is proposed to consider its properties from the same 
point of view as those of the other alkaloids. 

Quinine was isolated, together with cinchonine, by Pelletier 
and Caventou in 1820, and as a result of the labours of many 
chemists, of whom Skraup, Konigs, von Miller, and Ehode may 
be specially mentioned, the following formula has been gener- 
ally accepted to represent its constitution — 

H .N 



HO— CH 



CH3O 




that of cinchonine only dififering from it by the absence of the 
methoxy group, ( — OCH3), and that of cupreine only in having 
this group replaced by an hydroxyl group, (OH). 

The earlier attempts to prepare substances which should re- 
semble quinine in their properties were based on the assump- 
tion that the quinoline nucleus was the active portion of the 



ALKALOIDS 83 

molecule, but Fraenkel ^ brings forward many facts in support 
of tke view that it is the piperidine ring, the so-called '' loiponic 
acid portion " of the molecule, which is the true " pharmaco- 
phore." Thus, it is pointed out that in nicotine — 



(y 



GB.2 CH2 



CH CHj 



k 



N N 



i 



the contraction of the blood-vessels is almost certainly due to 
the pyrrolidine and not to the pyridine ring, seeing that this 
action is not shown by pyridine at all, but is produced by 
piperidine— 

CH, 

/ \ 

CII2 C)H2 

G3.2 C/M2 

\ / 
NH 

pyrrolidine, and N.-methyl pyrrolidine — 

GM2 CBLj 



CB.2 CS2 

\ / 

N 



h 



the last named closely resembling nicotine in this respect.^ In 
the same way it is considered that the action of quinine is due 
to the reduced piperidine ring, which is rendered still more 
active by the presence of the unsaturated group, — CH=GH2. 
The weak and uncertain action of cinchonine, compared with 
that of quinine, is probably owing to the absence of the para- 
methoxy group leaving the molecule without an " anchoring " 
group. Owing to this, the hydrogen atom of the quinoline 

1 '• Araneimittel-Bynthese/' p. 231 (1906). 

*TunniclifEe and Bosenbeim, Centralbl, fUr Physiol, 16 (1902), 93. 

6* 



84 SYNTHETIC DRUGS 

nucleus probably has to become oxidized to OH with the for- 
mation of cupreine before it can exert the characteristic quinine 
action. 

Many attempts have been made to prepare derivatives of 
quinine which should be free from some of its unpleasant by- 
efibcts, especially its bitter taste, and also to prepare derivatives 
which should be more soluble than the generally used sulphate, 
and so be suitable for hypodermic injection. Of the latter class, 
mention should be made of the double chloride and sulphate of 
quinine, which is very soluble in water, and of the double 
chloride of quinine and caffeine, which is readily soluble and 
suitable for hypodermic injection. Cinchonine is less bitter 
than quinine, but its action is weak and untrustworthy, and so 
it is not a suitable substitute. If quinine is converted into in- 
soluble derivatives its taste is diminished, and- a favourite de- 
rivative of this class is the tennate, which is practically tasteless, 
but suffers from the drawback that it is only slowly split up in 
the intestine into its components, and is therefore lacking in 
promptitude and certainty. 

Other derivatives have been prepared by esterification of the 
hydroxyl group, the most important of these being the esters of 
carbonic acid.^ The diquinine ester of carbonic acid 

CjjoHajNaO— 0— CO— 0— CjoHagNjO, 

is known as Arisiioquimne^ and is comparatively tasteless and 
fairly insoluble.^ Euquinine is the ethyl carbonate of quinine — 

. O-C^H, 

CO 

\ 

O— CjoH^sNaO 

and is prepared by the action of ethyl chloro-formate, CI. 
COOC^Hg, on quinine.^ It is practically tasteless, and does not 
have a bitter after-taste. The hydrochloride, on the other hand, 
is not as good as the free base, and has no advantage over 
quinine itself. 
Phenelidine quinine carbonic ester — 

1 D. B. P., 90,848, 93,698, 118,122. 

> Ibid., 184,307, 134,808. ' Ibid., 91.370. 



ALKALOIDS 8j 

NH— C-H.— OO^Hj 

/ 
CO 

\ 

— CjQHasNjO 

is known as Qmnaphenin, 

Saloquinine is the salioylio acid ester of quinine — 

OH 
/ 

\ 
CO— OC20H23N2O 

and is tasteless. 

QuiriOifphtlml is quinine ^-naphthol-sulphonate, and Quina- 
form ia quinine formate. 

In all these compounds, absence of taste is conditioned only 
by insolubility, their more soluble derivatives having the charac- 
teristic bitter taste of quinine. The more soluble hydrochloride 
of euquinine is an instance of this. 



CHAPTER Vn. 

ATROPINE AND THE TROPEINES— COCAINE AND THE LOCAL 

ANESTHETICS. 

Atbopine and cocaine are closely related, not only in their 
chemical constitution, but also in their physiological action, 

* 

both of them causing dilatation of the pupil (mydriatic action). 

Atropine and the Tropeines. — Atropine was discovered in 
1831 in the roots of the belladonna plant, and is a strongly 
poisonous alkaloid. Its chief use in medicine depends upon its 
action in dilating the pupil and paralysing the accommodation 
of the eye, and it is also used to check the inhibition of the 
heart arising from administration of chloroform and the depres- 
sant action of morphine on the respiratory centre. 

Atropine is an ester, and on hydrolysis 3nields a basic sub- 
stance, tropins, an optically inactive tropic acid.^ It has been 
shown that the alkaloid hyoscyamine, which is also obtained 
from belladonna and is IsBvo-rotatory, is the ester of tropine with 
IsBvo tropic acid,^ and therefore atropine appears to be racemic 
hyoscyamine. This view of the nature of atropine has been 
confirmed by Ladenburg,^ and dextro-hyoscyamine has also 
been prepared by the union of tropine vdth dextro tropic acid.* 

The pharmacology of these three stereo-isomerides, d.-hyos- 
cyamine, Z.-hyoscyamine, and the racemic form, atropine, has 
been investigated by Gushny,'^ using the frog as the subject of the 
experiments. It was found that all three were alike in certain 
respects, but that with regard to some aspects of their action, 

1 Kraut, AnndUn, 128 (1863), 273; 133 (1865), 87; 148 (1868), 236. 
LoBsen, AnnaUn, 131 (1864J, 43; 138, 230. 
3 Gadamer, A. Pharm., 239 (1901), 294. 
3 Ladenburg, Ber., 21 (1888), 3065. 
* Amenomiya, A, Phartn,, 240 (1902), 498. 
»Oushny, Joum. of Physiol, 30 (1903), 176. 

86 



ATROPINE AND THE TROPE INES 87 

dextro-hyoBcyamine was the strongest and the laBvo variety the 
weakest, while with other effects of the drug exactly the reverse 
was the case. In all cases the action of atropine was inter- 
mediate between that of the two optically active forms, and this 
fact is explained by Cushny by the assumption that atropine is 
probably decomposed in solution into its two active components. 

As atropine is the ester of tropine with racemic tropic acid, 
it is obvious that a knowledge of the constitution of these two 
substances is necessary in order to know that of atropine. 

Tropic acid is a relatively simple substance, being indeed a 
homologue of mandelic acid, and having the constitution — 

H 

an.— c— c©0H 



'6-^6 



A 



1"' 

OH 

This view of its strticture has been confirmed by a synthesis of 
the acid.^ 

The question of the constitution of tropine is one which has 
presented far greater difficulties, but thanks to the researches of 
Ladenburg, Merling, Willstatter, and others, our knowledge of 
the constitution of this substance is as complete as that of any 
alkaloid, and there is no doubt that it is represented by the 
formula — 

CII2 — ^CH — CM2 



i 



CHo — Cm — CS«i 



— CH3 CH— OH 



-2 ^-^ ^-^2 I 



and this has been confirmed by Willstatter's brilliant synthesis.^ 
The constitution of this substance is of great importance, as 
not only does it show that atropine and hyoscyamine are repre- 
sented by the formula — 

1 Ladenburg and Biigheimer, Ber,, 13 (1880), 876; Armaien, 217 (1880), 
74. 

sWUlBtatter and Iglauer, Ber,, 33 (1900), 1170; Willstatter, Ber., 34 
(1901), 129, 8163; Ibid. , Armalen, 317 (1901), 307. 



88 SYNTHETIC DRUGS 



6 



N— CH3 CH— O— CO— CH 

CHj CH CHj CHj— OH 

bnt it also explains the constitution of many other alkaloids 
¥^ioh are derivatives of it. 

For example, when tropine is heated with sodium and amyl 
alcohol, it is converted into a substance which is stereo-isomeric 
with it,^ and which is identical with the substance pseudo-tropine, 
obtained by the hydrolysis of the coca alkaloid, tropa-cocaine 
(benzoyl-pseudo-tropine).* Both tropine and pseudo-tropine 
yield the same substance on oxidation, namely trbpinone, and 
this on reduction yields pseudo-tropine and not tropine itself. 

GM^ CH CM2 CH2 CH  — CHj 

N— CH, CO N— CHj CH. 



CH 



OH 
-CH — CHo CHo Cj 



H CH— COOH 



2 ^^ ^^2 ^-^2 

Tropinone. Ecgonine. 

It has been shown that cocaine is a derivative of ecgonine, 
which is in turn a carboxylic acid of tropine, and hence our 
knowledge of the constitution of this important alkaloid is also 
dependent on that of tropine. 

Having accomplished the synthesis of atropine by combining 
tropine with tropic acid, Ladenburg prepared other esters of 
tropine with various organic acids, to which he gave the name ' 
tropeines.^ Other tropeines have been prepared by Merck, 
Ladenburg, and others, and these substances are of great interest, 
as their mydriatic action can be easily compared, and hence 
they afiford a convenient series of compounds for studying the 
relation between chemical constitution and physiological action. 
It was found that the tropeines derived from benzoic and cinna- 
mic acids were without mydriatic action, as also was that from 

^ Tropine is optically inactive, and so also is pseudo-tropine ; the isomer- 
ism is dependent on molecular asymmetry (cis-trans isomerism). — (Barrow- 
clifi and Tutin, J. C. 5., 96 (1909), 1966.) 

' For further details of these processes, see next section on Cocaine and 

Local A n flft tttiTi ftfei p.H 

^Ber., 13 (1880)* 106, 1080, 1137, 1649; 15 (1882), 1026; 22 (1889), 2690; 
Annalen, 217 (1880), 74. 



ATROPINE AND THE TROPEINES S9 


t 

laotio acid, but those derived from mandelic and atrolactinic 
acid possess mydriatio properties. 

H CH, 

CgHi^N— O— CO— C— CeHg C^Hi^N— O— CO— C— CeHj 

OH OH 

Mandelic. Atrolactinic. 

It will be noticed that the substances mentioned as having a 
mydriatic action, all contain both a benzene ring and an 
aliphatic hydroxyl group in the side chain containing the 
— O — CO group, and a statement has found its way into a good 
deal of the literature of the subject under the name of '* Laden- 
burg's Eule/' that only those tropeines which possess these 
characteristics have a mydriatic action. The so-called rule was 
never enunciated by Ladenburg, and it has been shown by 
Jowett and Pyman to be incorrect.^ For example, they found 
that the following three tropeines all have a mydriatic action : 
a-hydroxy-j8-2 pyridyl-propionyl tropeine — 

OH 

I 
-CHg— CH— CO— O— CgHi.N, 



^=r 



ortho-hydroxy-benzoyl tropeine (salicyl tropeine), 

<CI>-0O-O-0gH„N, 
OH 

meta-hydroxy-benzoyl tropeine, 

O-CO-0— CgH„N, 
HO 

although the first contains no benzene nucleus, and the second 
and third no aliphatic hydroxyl group. 

The tropeine derived from mandelic acid is known as homa- 
tropine,^ as it is tiie lower homologue of atropine — 

OgHi^N-^— CO— CH(OH)— CjHb 

Homatropine. 

CgHi.N- 0— CO— CH(CH2 . OH)— C^Hg 

Atropine. 
1 /. C. S., 95 (1909), 1090. » D, R. p,^ 96,853. 



90 SYNTHETIC DRUGS 

It is widely used in ophthalmic praotioe as a substitute for 
atropine, as its mydriatic action is nearly as great, and it has 
the advantages of being less toxic; moreover, its mydriatic 
action develops and passes off more rapidly. 

Other esters have been prepared which resemble the tropeines 
to some extent in their chemical structure, and also have a 
mydriatic action, namely, the esters derived from triacetone- 
methyl-alkamine, and its lower homologue vinyl diacetone 
alkamine. 

(CH3)2C CHg (CH3)2C CHj 

/ \ / \ 

N— CH, CH.OH N— CH, CH— OH 

„ \ / \ / 

(CHjjjC— — — CH2 CHgCH— — — CH2 

The structure of these substances is closely related to that of 
tropine. The former is prepared by reduction and methylation 
of triacetonamine — ^ 

(^^3)2^ — CH.^ (CHg)2C — ^CH2 (CH3)2C CH2 

/ \ / \ / \ 

NH CO -* NH CHOH -> N— CHj CHOH 

\ / \ / \ / 
(CHj)2C — CH2 (CH3)2C — CH2 (0113)20 ^0H2 

a process carried out by Fischer,^ who also showed the relation 
between this substance and tropine. Its ester with mandelic 
acid resembles homatropine and atropine in having mydriatic 
action. 

The preparation of N.-methyl-vinyl-diacetone-alkamine and 
some of its derivatives will be described later in connection with 
substitutes for cocaine, but for the present attention need only 
be drawn to the fact that various derivatives of the tropeine 
type have been prepared from it,^ some of which have a mydri- 
atic action. This substance, methyl-vinyl-diacetonamine, exists 
in two forms, one, a, melting at 137-138" 0., and the other, P, 
melting at 160-161° 0. The existence of two asymmetric carbon 
atoms (*) — 

1 Heinz, Annalen, Igg, 214 ; 191, 124 ; 198, 69. ^ 

« Fischer, Ber., 16 (1883), 1604, 2236 ; 17 (1884), 1797. I 

>Hames, AnnaUn, 294 (1896), 336; 296 (1897), 328. 



COCAINE AND THE LOCAL ANJESTHBTJCS gt 

(CH,)2C CH, 

/ \ 

CH,— N CH— OH 



 



C CH2 

/\ 

CH3 H 

in the molecule explains the existence of these two forms as 
stereo-isomerides, and it is interesting to note that it is only the 
mandelic ester derived from the ^-derivative which possesses 
mydriatic properties.^ This furnishes an interesting example 
of the difference in physiological action of stereo-isomerides. 

Cocaine and the Local Anaesthetics. — ^The alkaloid cocaine 
was discovered in coca leaves in 1860.^ It had long heen 
known that the South American Indians were in the habit of 
chewing these leaves as a stimulant to enable them to stand 
great exertion without fatigue. The first use of cocaine in this 
country was for a similar purpose, but its great importance 
among alkaloids at the present time is due chiefly to Roller's 
important discovery that cocaine is a powerful and rapid local 
anaesthetic. 

By hydrolysis with alkalies, cocaine yields ecgonine, benzoic 
acid, and methyl alcohol. Ecgonine was shown by Willstatter 
to be a carboxylic acid of tropine — 



t: 



1. 



CH _ 

CH— COOH 

N— CH, CH— OH . { 4 .J. / j 

CH, .u ^' 




(K.'vs^-'''^"'''^^ 



and by treatment with benzoyl chloride to yield benzoyl- 
eogonine, in which the hydroxyl group is converted into 
— CO . CfHj ; this on conversion into its methyl ester yields 
V cocaine, which therefore has the formula — 

1 Harries, Ber., 29 (1896), 2730. 

* Neumann, ilnnalm, 140 (I860), 218. 



^ 

V 



9a 



SYNTHETIC DRVOS 



CH, 
CH. 



CH \ 

/ I -— OH-COOp^ 

N— CH, CH— O— CO— C^ 



\ 



•J 



«"6 



H 



CH. 



2 



It is found that the free carboii^lic acid, benzoyl-ecgonine 
itself, has no local anaesthetic action, but that any of its alkyl 
esters, such as ethyl, propyl, etc., resemble its methyl ester, 
cocaine, in having this action.^ This applies only to the 
aliphatic esters, as the aromatic do not appear to have been 
prepared as yet. The effect of esterification is probably 
accounted for by an alteration of the anchoring group. 




N— CHj CH— O— CO— CeHfi 



Benzoyl ecgonine (type of first series of esters). 



CHc 




<j) 



CH— COOCH 



^— CH, CH— ( 



s 



^2 



Ecgonine methyl ester (type of second series of esters). 

Ecgonine can be esterified in the usual way, leaving Oxe 
hydroxyl group intact, and in this manner another series of 
esters can be obtained. Ecgonine methyl ester has no local 
anaesthetic action, but can be converted into cocaine by ben- 
zoylating the hydroxyl group. In this case, however, the nature 
of the group used to esterify the hydroxyl is important, for if the 
benzoyl group is replaced by others, the anaesthetic property is 
lost or greatly diminished. 



1 Merck. Ber., 18 (1886), 2964 ; 21 (l688), 48 ; Novy, Amer. Chem. Joum,, 
10 (1888), 147. 



COCAINE AND THE LOCAL ANAESTHETICS 93 

• 

Thus truxilline ^ (isatropyl-cocaine) has no ansBsthetic action, 
but is a strong cardiac poison, and Ehrlich^ found that, of 
several different cocaine derivatives, such as isatropyl-cocaine, 
valeryl-cocaine hydriodide, and phenylacetyl-cocaine hydriodide, 
the last named was the only one which had ansBsthetic proper- 
ties, but to a less degree than cocaine. All of these have a 
characteristic toxic effect on the liver, and differ from cocaine 
only in having the benzoyl group replaced by the one named. 

Cocoa leaves, which are the only commercial source of cocaine, 
contain various other alkaloids, most of which are, however, de- 
void of the useful physiological properties of cocaine. These 
other alkaloids are amorphous substances which yield ecgonine 
on hydrolysis, and therefore, owing to the high price of cocaine, 
various methods have been devised to utHize them in improving 
the yield of cocaine obtainable from the leaves. According to 
one method,^ the alcoholic solution of the amorphous bases is 
boiled with hydrochloric acid, filtered from the precipitated 
organic acids, and practically pure ecgonine hydrochloride 
obtained by evaporation of the filtrate. By means of benzoyl 
chloride or benzoic anhydride, this is converted into benzoyl- 
ecgonine, which is then esterified with methyl alcohol giving 
cocaine. Various modifications of this method have also been 
devised.* 

Cocaine has several disadvantages when used for hypodermic 
injection, one of the most serious being that its solutions do not f 
keep well, but become mouldy and decompose on boiling, so 
that they cannot be readily sterilized. For this reason, and 
also on account of the high price of cocaine, ^various attempts 
have been made to prepare analogous compounds which it was 
hoped would resemble cocaine in its useful physiological effects. 
As cocaine is a derivative of ecgonine, which is closely related 
to tropine, and as atropine, one of the esters of tropine, has a 
slight anaesthetic action, various attempts have been made to 
prepare substances from tropine which should have an action 
resembling that of cocaine. Several synthetic tropeines have 

^ Liebermonn, Ber,, 21 (1888), 2347. 
"Ehrlich, D^uUchs med. W., 32 (1891), 717. 
>Liebermann and Qiesel, D. B. P., 47,602. 

* Einhom and Klein, Ber,, 21, 3886 ; D. R. P., 47,713. Farbw. Hoechst, 
D. R. P., 76,483. 



94 SYNTHETIC DRUGS 

r^been prepared, and have already been discussed, but none of 
these are of value as substitutes for cocaine. Strangely enough, 
however, a natural tropeine was discovered in Java coca leaves,^ 
which is a stronger local ansesthetic than cocaine.^ This sub- 
stance, which is called tropacocaine^ also has the advantage 
over cocaine in being less toxic and more resistant to micro- 
organisms, and hence its solutions can be preserved for some 
(length of time. It is the benzoyl ester of pseudo-tropine,' which 
only differs from ordinary tropine in its space configuration. 
It differs from cocaine and atropine in having no mydriatic 
action, and in this respect it resembles the other pseudo-tropeines, 
such as those of mandelic acid and tropic acid. 

il will thus be seen that the tropeines derived from tropine 
itself have a strong mydriatic action, but only a weak anaesthetic 
action, while their stereo-isomerides, derived from pseudo-tropine, 
have no mydriatic action, but are powerful local anaesthetics. 

Pseudo-tropine is obtained from tropine by heating it with 
sodium amylate,^ and it is also obtained from tropinone — 




by electrolytic reduction in acid solution.'^ 

It should be pointed out that tropinone is obtained by oxidiz- 
ing tropine with chromic acid,^ or with permanganate in cold 
strong acid ^ solution, or with other oxidizing agents.* Pseudo- 
tropine is then easily converted into tropacocaine by means of 
benzoyl chloride. 

1 Giesel, Pharm, Ztg. (1891), 149. 

aChftdbourne, B. M, J, (1892), 402. 

3Liebermann, Ber,, 24 (1891), 2336, 2587 ; 25 (1892), 927. 

* D. R. P.. 88,270. » Ibid,, 116,517. 

8 Willstatter, Ber., 29 (1896), 896. ? D. R. P., 117,628. 

^Ibid., 117,629, 117,630, 118,607. 



COCAINE AND THE LOCAL ANJESTHETICS 



95 



CH 



CH 



CH. 



/ 



h 



N— GH 



H 



i 



\ 



3 



CH- 

Tropinone. 



OH, 

\ 
CO 

/ 
CH, 



CH 



/ 



« 



> I N— CH 



CH, I 



3 



H 

Pseudo-tropine. . 



CH, 

\ 
CH— OH 

/ 

CH, 1^ 




-CO— C,Hi 



Tropaoooaine. 

By the action of HCN on tropinone, Willstatter^ obtained 
the cyanhydrin — 



CH 



i 



2 



H, 



CH 
/ "^CHi 

N-CH3 \^c^ 

1 \CN 
\ ^CH, 

CH 



which on hydrolysis yielded 



CH 



CH, 



/ 



<! 



CH 



2 



H 



2 



N-CH., V°° 



\ 



CH' 



CH 



2 



which only differs from ecgonine in having the carboxyl group 
and the hydroxy! group united to the same carbon atom. He 
termed this substance a-ecgonvne, and from it he prepared by 
benzoylation and methylation a substance, a-cocaine — 



WillBtatter, B^., 29 (1896), 1575, 2216. 



96 



SYNTHETIC DRUGS 



< 



CH 



/ 



CH CH, 



8 



N— CH, 



C 



.COOCH, 



CH, 



\ 



CH CH, 



\0— CO— C«Hs 



which is, as would be expected from its close stnictviral relation 
to it, very much like cocaine itself in its chemical properties, 
such as the oystallizing power of its eaiia, but strangely enough, 
!■ it is totally devoid of anassthetic properties. 

Although a-oooaine does not possess anaesthetic properties, a 
similar a compound derived from N-methyl-triacetone-alkamine 
was found to be a vs^uable local ansasthetic. 



CH 



CH 



/ 



2 



N— CH, 





CH. 



-CH — GS( 



/COOCH, 
CH,— N C\V^ 



CH, 



^::=co=-cyEs 



CH — CH« 



o-oooame. 



CH, 



CH,-i 



CH, 



CH 



3" 



A 



-CH, 



-CH 



N— CH 



CH 



A 



1 



CH.OH 
-CH, 



CH,— N 



C 



.COOCH, 



6-^6 



I 

CH 



CH,-- 



t 



<i 



^0— CO— 0«H 
CHj 



H 



3 

a-6uoaine. 



N-methyl-triftoetone-alkamine. 

The substance in question is known as a-eticaine, and was 
obtained by Merling in the following manner.^ Three molecules 
of acetone were allowed to react with one of ammonia, giving 
triacetonamine, which on treatment with HCN yields the 
cyanhydrin. This on hydrolysis yields triacetone-alkamine- 
carboxylic acid, which on benzoylation and methylation yields 
N-methyl-benzoyl'triacetone-alkamine-carbozylic acid methyl 
ester (a-eucaine). 

» Merling, B#r. deut. Pharm. Geselkchaft, 6 (1897), 178. 



V 



COCAINE AND THE LOCAL ANESTHETICS 97 

3(CH3),CO (CH,)3C-CH, (CH,),C CHg 

> I I " I I /OH 

+ NH3 NH CO HON NH < 

1 I I |\0N 

(0^3)2^ ^-^2 (^33)20 CH2 

(033)20 — vSj (033)20 — OH2 

^ I I /OH ► I J .O.OO.OeHg 

NH C( CH3— N < 

I I \000H I I \OOOOH3 

(^■^3)2^ 0^2 (0^3)2^ ^^2 

This substance is a cheap substitute for cocaine, and it has 
the advantage of being less toxic and of being stable to boiling 
water, so that its solutions can be sterilized by boiling. It has 
the drawback of being somewhat painful and irritant when 
injeqted, and it has now been superseded by P-eucaine} the 
hydrochloride of benzoyl-vinyl-diacetone-alkamine — 

i OH, 



'8 



OH3 — OH2 



H— N OH— 0— 00— CgHj 

CH3 — OH — OH2 

This substance is stable to boiling water and so can be readily 
sterilized. It is less toxic than a-eucaine, and is easily sol- 
uble in water, the lactate, which is often used instead of the 
hydrochloride, being soluble up to 30 per cent. It is equal 
to cocaine iii its anaesthetic properties, and is widely used in 
many branches of surgery. Yinyl-diacetonamine, the parent 
substance of ^-eucaine, was obtained by Harries by the inter- 
action of diacetonamine and acetaldehyde,^ but it is obtained 
in better yield by boiling the acid oxalate of diacetonamine 
with diethylaoetal in alcoholic solution.' 

The yinyl-diacetonamine, on reduction with sodium amal- 
gam,^ yields a mixture of the two isomeric {cis and trans) 
vinyl-diacetone-alkamines. 

> D. R. P., 90,069. 

s Harries, Annalen, 296 (1897), 828 ; 299 (1898), 846. 
»B. P., 101,738(1916). 

«E. Fischer, Ber., 17 (1884), 1794; Harries, Annaien, 294 (1897), 872; 
D. R. P., 95,622. 

7 



»1^, 



98 



SYNTHETIC DRUGS 



This mixture is eotiyerted into the stable isomer of lower 
melting point by boiling with sodium amylate,^ which is then 
converted into the base of )3-eucaine by treatment with benzoyl 
chloride.2 




CH, ; 




Tt 


+ 





+ 


H 



CO 



CH, 



CH, CHj 



,6] 



00 
/ \ 

gm^ Cm 



C(CH,) 



3 



NH. 



C(CH,), 

/ 
NHj 



CH, ."CHO I 

CH,-C— H C(CH,)s, 



2 (Acetone) + Ammoni». Oiaoetonamine. 



\ / 
NH 



Vinyl-disicetonftinine. 



Bednotion. 



CH.O 
GHo GSo 



CO . CeH, 



CH,— CH 



C^HjCO . CI 



CH.OH 
GM2 GHq 



C(CH,), 



NH 
Base of iS-eucaine. 



CH3— CH C(CH3)2 

\/ 
NH 

Vinyl-diaoetone-alkamine. 



Besides the members of the cocaine series and the acetone- 
alkamines, there are a large number of other substances pos- 
sessing local ansBsthetic properties. Many of the antipyretics 
of the aniline type have this property, and in the case of 
phenetidine derivatives, the ansBsthetic character of the sub- 
stance is greatly enhanced by combination with a second 
base. Hohcaine, one of the best known substances of this 
type, is the mono-hydrochloride of — 

^xx „^n-c,h,-o-c,h; 

CH,— Cf 

\nH— CgH^- 0— C^5 



»D.R. P., 96,621. 



»/6i<»., 97,672. 



COCAINE AND THE LOCAL ANESTHETICS gg 

It is prepared by oondensing phenetidine with phenaoetin ' — 
IH,;— N— CgH,— O— CjHg 

+ i / 

CH,— CjO/ — NH— CgH^— O— CjHj 

= CH _(3/'N-^«^«-°-*^»^» + H,0 
* NnH— CgH^— 0— CjHj 

Holooaine has the drawbacks of being more toxic than cocaine, 
and ot being sparingly soluble in water ; but, on the other 
hand, its aqueous solutions keep well, and have a rapid 
ansasthetio action. It is used in ophthalmic surgery. 

In recent years attention has been directed chiefly to al- 
kamine esters, which contain the grouping— 

B 

III. 
_N— 0— C— 0— CO— E' 

I I I 

a grouping very similar to that indicated by asterisks {*) in 
the formula for cocaine.^ 



CHs— CH-: — CH— COOCH 



CHj — CH CH2 



3 

3 yxx \j VJ\J v^fl-u-S 



CH, ch— o— CO— ds 



Stovaine, alypine, and novoeaine are well-known members of 
the group. Stovaine — 

CHg O— CO— C^Hfi 

C 

/\ 

C2H5 CH2-N(CH3)2, HCl 

is a well-known synthetic anesthetic, obtained by the action 
of magnesium-ethyl-bromide on di^hyl-amino-acetone, and 
bepzoylation of the product thus obtained. 

1 D. R. P., 79.868, 80,568. « Pyman. /. C. S., 93 (1908), 37^, . . : 

*. 7 <*  : 



loo SYNTHETIC DRUGS 

CH, Br— Mg— CjHs CH, 

CO > 



OH,— 



». C»H.— C— OH 

I 
N(CH,), CH,-N(CH,), 

CH, 



'8 



 C2H5— C— O— CO— CjH, 



CHj— N(CH,)j 

It is very widely used for producing spinal anaesthesia. 

Alypine is the hydrochloride of tetrametbyl-diamino-di- 
methyl-ethyl-carbinyl benzoate — 

CH2-N(CH,), 



,— C— 0— CO— ( 

CH3-N(CH,)5 



C2H5— C— 0— CO— C«H, 



and is therefore similar to stovaine in its constitution, being 
the dimethyl-amino derivative of the latter. 

As a looal ansBsthetic, it is said to have the useful properties 
of cocaine without most of its drawbacks, producing rapid 
ansBsthesia, and being free from injurious effects on the heart 
and respiration. 

A whole series of local anaasthetics which also possess anti- 
{ septic properties has been discovered by Einhorn and Heintz.^ 
They found that the benzoyl derivative of amino-hydroxy-ben- 
zoic ester possessed distinct ansBsthetic properties, and contrary 
to the behaviour of cocaine, the removal of the benzoyl group 
yielded a substance of which the anaasthetic properties were 
greater than those of the benzoyl derivative. A large number 
of substances of this type were produced, of which ^-amino-m- 

H N/\ ' 

hydroxy-benzoic-methyl-ester, ^ T JcOOCH ' ^^s intro- 
duced into practice under the name of Orthoform, It is a 
white powder, very slightly soluble in water, which is non- 

1 Mmohen^ m$d, TT., 34 (1897), 931 ; Annalm, 311, 26, 164 ; 325, 805 ; 
359.. l^ h 371, 125, 181, 142, 162 (1900-1909). 



COCAINE AND THE LOCAL ANESTHETICS loi 

toxic and has no action on the unbroken skin, but produces 
anaesthesia on coming into contact with the peripheral nerves 
themselves. It is used as a dusting powder for painful wounds, 
etc. The high price of orthoform led to the production of an 

" "" ' NBD^COOCHg 
isomeric substance, ttq , called New Orthoform, 

which has the same physiological action, but is cheaper.^ 

These compounds are not sufficiently soluble to be adminis- 
tered h3rpodermically, and their more soluble hydrochlorides 
are too strongly acid for this purpose. To overcome this de- 
fect, Einhorn has prepared various derivatives of glycocoU 
with different amino-hydroxybenzoic acids. 

/NHs 
HO— Aryl groups + HO . CO— CHj— NE'» 

\COOE 

Amino-hTdrozybenzoic acid + GlyooooU derivative 



/ 



NH . CO . CHo^NE' 



=*H0 — Aryl groups;" 

\COOE 



2 



+ H,0 



These compounds differ from the parent substances in being 
strongly basic, and hence they can form soluble salts (such as 
hydrochlorides) of neutral reaction. Their ansssthetic action 
is not closely related to that of the parent substance. A large 
number of these compounds have been prepared,^ and the 

ANH2 
diethyl-glycocoU derivative of -d-qI I i"" having the formula 

COOCH3 
/\NH . CO . CHa— N(CH8)2 



HO 



COOCH3 



has been introduced into therapeutics, in the form of its 

hydrochloride, under the name of Nirvanine,^ It is easily 

soluble, and is less toxic than orthoform, which it resembles 
in its general behaviour. 

* D. R. P. 97 333 97 334 111 932. 

a Ibid.', 106,602, 108.027, *108,871. ^ MUnchener med, TT., 49 (1898). 



\ 



102 SYNTHETIC DRUGS 

The simplest local anaesthetic of this type is ethyl para- 

amino-benzoate, NH ^ X ^OOC^Hfi, known as Anasthesine. 
It resembles orthoform in most of its properties, and is said to 
be free from any toxic action. It is insoluble in cold water, 
but its solution in olive-oil may be used for hypodermic in- 
jection. Its salt with'para-phenolsulphonic acid, 

NHj, . CeH^ . COOC2HB, HO . CgH^ . BO3H, 

is soluble in water, and has been used for hypodermic injec- 
tion under the name of Subcutin. 

The isobutyl ester of p-amino-benzoic aeid 

NHg . CgH^ . COOC4H9 

has also been suggested as a local ansBsthetic under the name 
of Cychform, 

Novocaine is the hydrochloride of the diethylamine deriva- 
tive of ansesthesine, having the formula — 

NH2<CI>— C0~0— CHj— CH2N(C2H5)2,HC1 

which, it will be seen, contains the previously mentioned 
grouping — " 

B'— CO— 0— C— C— NE— 



It is a non-irritant and powerful local anaesthetic, only one- 
seventh as toxic as cocaine, and of recent years has found 
very extended use, so that it is now the most valued of all 
local anaesthetics. 

The preparation of novocaine can be carried out in various 
ways,^ but all the methods are somewhat difficult, involving 
the preparation of ethylene-chlorhydrin and of diethylamine, 
so that attention has recently been given to improvements in 
the production of the latter compound.^ 

Ethylene chlorhydrin, for example, may be heated with para- 
nitrobenzoyl chloride, and the resultant chlorethyl para-nitror 
benzoic ester, then heated with diethylamine for twenty-four 
hours in a closed vessel at 100-120'' C. The diethylaminoethyl 

1 D. B. P., 179,627, 180,291, 180,292; U. S. P., 812,564. 
2 J. S, C. J., 33 (1916), 147 ; J. C. S., 109 (1916), 174. 



COCAINE AND THE LOCAL ANAESTHETICS 103 

ester of para-nitrobenzoic acid so obtained is tben reduced 
with tin and hydrochloric acid to form novocaine. 

COCl HO— C2H4— CI CO . O— CH2— CH2— CI 








NO, KO, . 

CO . O . CHj . CHj . N(CjH4)s„ CO . O— CHj— CH,— N(CjHs)j • 



NH, sro 



0_ 



2 



Another method ^ is to condense ethylene chlorhydrin with 
diethylamine to form chlorethyl-diethylamine. 

CI— CHg— CH2— OH + HN(C2H5)3 

= CI— CHj— CH2— N(C2H5)2 + H2O. 

This is then heated with sodium para-aminobenzoate to 
form the base of novocaine. 



^2 



H2N<(~>C00Na + CI— CHj— CHg— NCCjHfi)^ 

« NaCl + H2N<[]3^00— CHj- CH2— N(C2H6)2. 

In a third variation,^ para-aminobenzoic acid is condensed 
with ethylene chlorhydrin by heating them to 100^ in sulphuric 
acid solution. The compound so obtained is then heated in a 
sealed tube with diethylamine at 100-110'' to form novocaine. 

• 

COOH HO— CH2— CHg— CI COO— CHj- CH2— CI + HgO 








i HN(C^j)j 

COO— CHg— CHj— N(C^j)^Cl 




NH, 

I D. B. P., 189,335. 'Ibid., 194,748. 



CHAPTER VIII. 

MORPmNE GROUP AND ISOQUINOLINE GROUPS OF 

ALKALOIDS. 

MOBPHINB GbOUP. 

MoBPHiNB is the most important of the opium alkaloids, and 
is the one to whioh most of the physiological effects of opium 
are due. The principal alkaloids present in opium may be 
divided into two well-defined groups : — 

(1) The Morphine Group, consisting of morphine, codeine, 
and thebaine, all of them very poisonous substances, and con- 
taining a phenanthrene nucleus, as well as a nitrogen ring. 

(2) The Papaverine Group, consisting of narcotine, papavar- 
ine, narceine, laudanosine, oxynarcotine, etc. These substances, 
which are derivatives of isoquinoline, are far less physiologi- 
cally active than those of the first group. These alkaloids and 
some of their derivatives will be considered in the next section, 
and for the present attention will be directed to the members 
of the first group. 

All the opium alkaloids produce nervous depression, begin- 
ning in the psychic centres of the brain, and extending down- 
wards through the various cerebral centres in the reverse 
order of the development, and they also have a strychnine- 
like action on the cord, giving rise to convulsions. In some 
of these alkaloids, such as morphine, the depressant {i,e, nar- 
cotic and analgesic) action predominates, twitchings or con- 
vulsions being extremely rare, while in others, such as thebaine, 
the convulsant action is far stronger, and practically masks 
the weak narcotic action. Codeine stands between the two, 
having marked narcotic properties, but in a weaker degree than 
morphine, while, on the other hand, it is more liable than 
morphine to give rise to increased reflexes and spasmodic 
twitchings. 

104 



ALKALOIDS: MORPHINE AND ISOQVINOLINE GROUPS 1O5 

The following table indicates which of these effects pre- 
dominates :— ^ 

Morphine (most narcotic), 

Papaverine, 

Codeine, 

Narcotine, 

Thebaine, 

Laudanine (most convulsant). 
Morphine has never been synthesized, and its structure is 
not even known with certainty, so that this section will deal 
mainly with the efforts that have been made to synthesize 
derivatives of morphine, which should differ from it in certain 
respects with regard to their physiological action, and also 
with the attempts that have been made to obtain synthetic 
products, which should possess a similar action to morphine 
owing to the presence of similar groupings in the molecule. 
These attempts are hampered by the fact that we do not know 
which portion of the molecule plays the chief part in de- 
termining the physiological action. 

Nevertheless, it is necessary to indicate the basis on which 
our knowledge of the structure of morphine rests. The formula 
of morphine is Ci^H^gOjN ; it is a tertiary base, and contains 
two hydroxyl groups, one of which is phenolic, and the other 
alcoholic in character. The alkaloid, codeine^ C^gHgiOgN, differs 
from morphine by Gn2, and as it contains one hydroxyl group,^ 
it therefore appeared probable that it was morphine in which 
the hydrogen of one of the hydroxyl groups had been replaced 
by GHj. This assumption was shown to be highly probable 
by the work of Matthiessen and Wright,^ and confirmed in 
1881 by Grimaux, who * converted morphine into codeine by 
direct methylation. Therefore the constitution of codeine and 
that of morphine can be considered together, the former being 
Ci7Hi70N(OH)(OCH3), and the latter Ci7Hi70N(OH)2; the 
complex C^jH^jON being the same in both, it is clear that a 
knowledge of this complex will reveal the structure of both 
alkaloids. 

1 Dixon, ** Manual of Pharmacology " (1906), p. 131. 
a Wright, /. 0. 8,y 27 (1874), 1031. 
» Matthiessen and Wright, J. C. S., 25 (1872), fi06. 
* Grimaux, C. B., 93 (1881), 591. 



io6 



SYNTHETIC DRUGS 



The study of this question h^ occupied the attention of many 
chemists, and thanks mainly to the labours of Vongerichten, 
Schrotter, Knorr, and Pschorr, we have guned a tolerably 
clear insight of the nature of this grouping. Vongerichten and 
Schrotter by distillation of morphine with zinc dust obtained 



HC 



phenanthrene, 




, together with pyrrol, HC 



CH, 



\ A 
NH 




pyridine, | 1 trimethylamine, N(Gn3)3, and ammonia. A de- 



tailed account of the numerous investigations that have been 
carried out on morphine and codeine is beyond the scope of 
this chapter ; an account of the recent work on this subject is 
given by Dr. H. B. Watt in Science Progress, 4, 279 (1909), 
and the reader desiring further information is referred to this 
and to Pictet's " Vegetable Alkaloids." As a result of his own 
and other investigations, Enorr has suggested the following 



formula ^ for morphine — 

CH, 



that of codeine being — 






^8 



CH 



/ 



s 



N 



CH 



i 



CH. 



CH 

in 

CH— O 
H— C CH 

\ 
OH 



CH 



/■x/ 



A 



2 



H. 



\ 



H 



CH 



CH 



.1, 



3 



m 



CH— 

H— C CH 

HO C 

\ 
O— CH, 



More recently Enorr has somewhat modified this formula, as 
shown below, and Pschorr, Jaeokel, and Fecht have sngg,ested 

' In all oases, an unoooupied comer such as /"\ represents / ^"^, and 



I. 



/% represents /^%. 



A. 



ALKALOIDS: MORPHINE AND tSOQUlNOLlNE GROUPS 107 



a formula for morphine whioh depicts it as a dbrirative of 
N.-methyl-piperidine. This formula is based on a study of 
apomorphine, G^^Hj^O^N, a dehydration product of morphine. 

CHjj 

^  \/ \ 

CH— N— GH. 



HO 



•^s 



\ /\ /\ CH 



\/ 



/ 



/ 







C, 



OH, 



/ 



GH, 





/\ 
H OH 

Knorr's later formala. 



GHj N— GHj 
CH CH 



CH. 



HO 



CH, 



I C— H 

0— C CH, 

/\/ 
H G 

/\ 
H OH 



HO 



L 

I 

I CH / 
6 CH, N/ 



H 



CH 



2 



Psohorr's formnla. 



CH, 
GH 

\ / 



/\ 
H OH 

Bnohetet's formula, modified by Enorr. 

An important difference between these iwo formulas and 
Knorr's earlier formula is that they show the and N in 
separate ring systems. Buoherer's formula, as modified by 
Enorr, is a link between the two types. In all of these codeine 
is the same but for the phenolic OH being replaced by OGH,. 



,N 



io8 



SYNTHETIC DRUC^S 



The alkaloid thebaine has been shown by the work of many 
investigators to be closely related to morphine and codeine. 



(Oi,H,,ONCH,)(OH), 

Morphine. 



(C„H„ON0H,)(OH)(OCH,) 

Codeine. 



(0„Hi,0N0H^(O0H,), 
Thebaine. 

It differs from morphine and codeine in having both the 
hydroxyl groups replaced by methoxy (OCH,) groups, and in 
having two atoms of hydrogen less in the rest of the molecule. 
Accordingly, if we accept Enorr's formula for codeine, we ob- 
tain the following formula for thebaine : — 



CH, 

CH— N— CH, 



CH,0 



\ /\ /'\ CH, 



CH / 
CH, 



6 



/ 



-C 



/ 



OH, 



CH.OH 



Codeine. 



CH 



i 



CH- 



OH,0 



•N— CH, 



\ /\ /\ CH, 



CH / 
CH 



O 



^ 



/ 



/ 

Cv ^ 
^COCH 



* 



Thebaine. 



ALKALOIDS: MORPHINE AND ISOQUINOLINE GROUPS 109 



and on the basis of Pschorr's formula for Qodeine, the corre- 
sponding formula for thebaine is as shown below — 



CHo N— CH 



^2 






i 



CH.0 



CHj N— CH, 
CH OH, 



i 



H 



C— H 

0—0 CHa 

/\/ 
H 

H OH 
Codeine. 



2 



^^»°\/\/ \/ 



i 



H 



i 



0— C C] 



H 



i 



Thebaine. 



OH, 



Of the various derivatives prepared from morphine which 
are used in medicine, the naturally occurring alkaloid codeine 
is the one which most closely resembles morphine. As already 
stated,, it was first prepared directly from morphine by 
Grimaux,^ who also prepared ethylmorphine (codethyline), but 
since then many other manufacturing methods have been de- 
vised in order to obtain better yields. It was first prepared 
on a large scale by Knoll,^ and Pechmann's method of methyla- 
tion by means of diazo-methane ^ has also been applied to the 
preparation of codeine from morphine/ but by this method also 
the yields do not appear to be very satisfactory. Methyl sul- 
phate is at the present time a favourite methylating agent, and 
Merck has devised a means of preparing codeine by the action 
of methyl sulphate on morphine in the presence of alcohol and 
sodium.'^ The neutral alkyl esters of phosphoric and nitric 
acids can also be used in the same way as the sulphate.^ 

The pharmacology of morphine, codeine, monacetyl-,diacetyl-, 
and benzoyl-morphine has been investigated by Stockman and 
Dott/ and that of the homologues of codeine, together with a 

iGrimaux, 0. 22., 92 (1881), 1140, 1228; 93 (1881), 67, 217, 691. 
' D B P 39 S87 

» Bir.,'27 (1894), 1888 ; 28 (1896), 866, 1624. ^ 
* D. R. P., 95,614, 9 ),146. » Ibid., 102,634. 

•J6«i., 107,226, 108,076. 

7 Stockman and Dott, B, M. J. (1881), 24th Jan. (18^), II. 189 : Proc. 
Roy. Soc. Edi)tb., 17 (1890), 321. 



no SYNTHETIC DRUGS 

large number of morphine derivatives by Mering.^ The action 
of the higher homologues of codeine is similar to but somewhat 
weaker than that of codeine itself. Codeine methyl bromide, 
GigHjiOsNCHgBr, or Eucodeine is said to be less toxic than 
codeine. Ethyl morphine is somewhat exceptional in having 
a stronger and more prolonged action than codeine, and is re- 
commended against irritant coughing. Its hydrochloride has 
been introduced into therapeutics under the name of Dionine. 
The benzyl (C^Hg — CHg) derivative of morphine also re- 
sembles codeine in its action, and has been introduced by 
Mering in the form of its hydrochloride, under the name of 
Peronine, It is obtained by the action of sodium ethoxide 
and benzyl chloride on morphine in alcoholic solution.^ 

The carbonic acid esters of morphine are very unstable, but 
the acyl derivatives are quite stable, and some of them have 
attained great practical importance. The acyl derivatives of 
morphine, in which only* the phenolic hydrogen is replaced, 
mono-acetyl-, propionyl- and benzoyl-morphines closely re- 
semble morphine itself in their physiological action, being 
intermediate between it and the diacetyl compounds to be 
described later. (It should be pointed out that in the case 
of codeine, dionine, and peronine, it is also the hydrogen of 
the phenolic hydroxyl which is replaced by CHj, CjHg and 
CgHg . CH3 respectively. These are phenolic ethers containing 
the group — OR, but monoacetyl-, propionyl-, and benzoyl- 
morphine are phenolic esters^ containing the group O — CO — R, 
and are more readily hydrolyzed than the ethers) The deriva- 
tives of morphine, in which both hydroxyl groups are esterified 
by acid radicles, have also been investigated by Mering. He 
investigated the diacetyl, di-propionyl, di-isobutyryl, and di- 
valeryl derivatives, and found, in confirmation of the work 
of Stockman and Dott, that these possessed a more decided 
narcotic action on dogs than codeine, and a stronger tetanic 
action than morphine. Clinically, they have proved valuable 
in lowering reflex irritability d.nd calming spasmodic coughing, 
but in checking pain they are less active than morphine. 
Under the names of Heroin and Acetomorphine, the diacetyl 

1 Mering, Merck's Jahresber, (1898), 5. » D. R. P., 91,813. 



ALKALOIDS: MORPHINE AND ISOQUINOLINE GROUPS iii 

derivative has attained considerable practical importance in 
checking coughing arising from irritation, etc. 

By the action of dehydrating agents, such as concentrated 

( HGl at l^O"" C, on morphine, a substance is formed which 

; differs from morphine by the elements of water, and is called 

i apomorphine, G^.^B.^gO^'N — ^H20-^Ci7Hi702N. It differs very 

i greatly from morphine in its physiological action, being a most 

I powerful emetic, and in large doses stimulating the respiratory 

centre, with consequent quickening of the rate of breathing. 

Its action is therefore quite different from that of morphine. 

The emetic action of this substance is not local, but is of 

central-nervous origin through stimulation of the medulla. In 

therapeutics the hydrochloride is usually used, and is given 

hypodermically, the dose being soon followed by vomiting 

without harmful by-effects. The fact that apomorphine can 

be given in this manner constitutes one of its chief advantages' 

over the peripheral emetics, which act locally on the alimentary 

canal. 

With regard to the chemical nature of apomorphine, it 
was first thought that one of the oxygen atoms was present 
in a hydroxyl group, and the other in an ether group, 

— ^C — O — U — , as only a mono-acetyl derivative had been 

I I 

prepared,^ but Pschorr, Jaeckel, and Fecht have shown that 
> both oxygen atoms are present as hydroxyl groups.^ 

HO/% 



HO 



N^NoH 



^2 



(YX^ 



GM2 CH.2 

They also prepared a monomethyl ether of apomorphine, which 
has been shown ^ to be identical with the so-called " pseudo "- 
apocodeine, obtained by heating codeine with anhydrous oxalic 
acid at 150° C* 

1 Dankwortt, Annalm, 228 (1886), 572. « Ber., 35 (1902), 4377. 

' Knorr and Baabe, Ber., 41 (1908), 3060. * Ber,, 40 (1907), 3366. 



112 SYNTHETIC DRUGS 

Apooodeine, codeine, apomorphine, and morphine all produce 
purgation in dogs and oats, but this action is greatest in apoco- 
deine, and diminishes in the order given down to morphine. 
In the case of apocodeine, the purgative action is greater than 
the vomiting, and it is stated, when given hypodermically in 
suitable doses, to produce purgation without vomiting, and its 
use as a hypodermic purgative has been suggested by Dixon.^ 
Such a substance is greatly needed, and should apocodeine 
come into use for this purpose, it would be one of the most 
important of artificial drugs. 

The endeavours that have been made to synthesize substances 
analogous to morphine do not appear to have been very success- 
ful. This is not surprising considering that, apart from any 
doubt as to the actual constitution of morphine, there is still no 
means of judging which part of the molecule is most intimately 
connected with the action of the substance. 

The early work of Knorr led him to the conclusion that 
morphine might be represented by the formula — ' 

CH . OH O 

^/ \ / \ 

CioH6(OH) CH CH2 

\ i i 

CH2 CH CH2 

\ / 

N 

CH, 

a conclusion which was subsequently disproved by his own 
work. 

Knorr gave the name ** morpholine " to the grouping — 

O 




CH2 CH2 
CH2 CH2 




NH 
> Dizon, B. M. J., 18th Oct., 1902. 



ALKALOIDS: MORPHINE AND ISOQVINOLINE GROUPS 113 



as he regarded it as the parent substance of morphine. A 
general method of preparing morpholine and its derivatives 
which was devised by Enorr,^ consists in splitting off water 
from dihydroxyethylamines by means of condensing agents, 
such as 70 per cent, sulphuric acid, acetic anhydride, etc. 
The dihydroxyethylamines are prepared by the condensation 
of ethylene-ozide with amines. 

CH2V CHjv vGH« — GH-n — OH 

I >0 + NH.+ I >0 « NH< 

P.TT / PTT / Nl 



^' 



^2" 



ca 



CH 



2 



CHa— CH,— OH 



oono. H2SO4 
— -> 



NH 



yCHj — CHgv 



\ 



GHa — GHi 



/ 



O 



The parent substance, morpholine itself, was prepared in 
this way, using HOI at 160" as the condensing agent.^ By 
using various primary amines of the type BNHg instead of 
ammonia, substituted morpholines of the type — 

yCHa CHgv 

ENC >0 

^CHa— CHa-^ 

may be obtained, and by using substituted derivatives of 

E— CHv 
ethylene-ozide, such as | ^0, derivatives of morpholine 



R— oh/ 



can be obtained, some of which are not unlike morphine in 
their properties. As an example, tetrahydro-naphthalene- 
morpholine may be mentioned, as it resembles morphine most 
closely.' It was obtained by condensing an alicyclic derivative 
of ethylene-oxide, namely, tetrahydro-naphthylene-oxide with 
hydroxyethylamine. 

OHj OH2 

Hoa 



^\/\ 



reduced 



\/\^ 



OH, 



CH 



^^^CHCl 

CH 
j alcoholic KOH 



1 Knorr, Ber., SO (1897). 909 ; 31 (1898), 1070, 1969 ; D. B. P., 95,854. 
3B^., 22(1889), 2081. 

'AnnaJen, SOI (1898), 1 ; S07 (1899), 171. 187 ; Ber., 32 (1899), 782. 

8 



"4 



SYNTHBTtC DRUGS 






\/\/ 



CH 



\0 NHr-CHr-OH^OH 



CHj OH OH 

^\X\ /. / 
CH CHj 



I 



CH 



2 



Tetrahydro-naphthylene-ozide. 



CH CHj 
CHjNH 

I HaS04 



CHa O 
CH ^^ 



2 



» I ' > 



CH, 



CH 

CH, NH 

Another method of preparing derivatives of tetrahydro- 
naphthalene-morpholine which has been devised by Knorr^ 
is by means of the action of hot dilute sulphuric acid on the 
hydramines of the naphthalene series. 



CHgOH OH 



CH CH2 
CH CH, 
CH,NR 



CH, 
/-\/\/\CH. 



CH 



k 



\/\/\y 



CH 



i 



CH,NE 



These hydramines can be obtained by the action of the 
ethanolaSnines on the chlorhydrin (see above), or on the oxide 
of dihydronaphthalene. 

CH. OH 



CH 

in 



OH 
CI 



CH, 



CH 

H CH 

\/ 
NB 



CH, 



OH OH 



a 



i 



CH 



1 



CH 

CH CH, 
CH, NR 



+ HCl 



A somewhat different method of obtaining a morpholine 
derivative has been devised by Stormer,' and consists in re- 

> D. B. P., 10{»,4S8. * Anndlen, 288 (1895), 89. 



ALKALOIDS: MORPHINE AND ISOQUINOLINE GROUPS 115 

ducing a boiling alooholio solutioh of ortho-nitro-phenacetol 
with tin and hydrochloric acid, whereby 2-inethyl-pheno mor- 
pholine is obtained. 

O / \ 

M CH,— CO.CH, -* M CHj 



\ 

NO, 



NHjCH— CH, 

\ \ / 







^2 



/ CHs 

\ CH— CH, 

NH 

Nitro-phenaoeiol is obtained by, the action of a piono-halogen 
ketone on the sodium salt of o.-nitrophenol.^ 

ONa XCHj— CO . CHj O 

0+ -NaX.+ n OH, 

NOg ^^NO, I 

00— CH, 

In a similar way a naphtho-morpholine may be obtained from — 



CO 



OH 



On the other hand, Vahlen ^ differs from Knorr, and considers 
that it is the phenanthrene portion of the molecule which is of 
greatest importance in determining the physiological action of 
morphine. (Overton has shown that phenanthrene itself has 
a narcotic action on tadpoles.) Vahlen considers that the 
'' pharmacophore " of morphine is the grouping — 





\ / 

C— — Cv 



» D. R. P., 97,242. « Vahlen, A.b.P^P., 47 (1901), 868. 



ii6 SYNTHETIC DRUGS 

and he prepared the hydrochloride of 9-amino lO-hydrozy- 
phenanthrene — 





\ / 

OH NHj, HCl 

which he called ** morphigenine/' and from this he obtained 



ti 



epiosine ** — 




\ / 

i J 




N N— CH, 

CH 

by heating it with sodium acetate, alcohol, and methylamine 
under pressure. Epiosine, which to a certain extent resembles 
morphine and codeine in some of its physiological effects, is 
identical with methyl-diphenylene-iminazole, which has also 
been prepared by other investigators.^ 

ISOQUINOLINB ALKALOIDS AND THBIB DeBIVATIVBS. 

The most important of the opium alkaloids have already been 
dealt with, but there are several others of some importance, 
most of which are derivatives of isoquinoline. These include 
narcotine, papaverine, narceine, laudanosine, and laudanine. 
The physiological action of these alkaloids is generally not so 
marked as that of the members of the morphine group. The 
important alkaloids of Hydrastis canadensis^ namely, hydrastine, 
berberine, and canadine, are also derivatives of isoquinoline, as 
also is corydaline, the chief alkaloid present in Gorydalis cava. 
Of these various alkaloids, hydrastine is probably the most 
important from the medical point of view, but various artificial 
alkaloids have been prepared from many members of this series 
by simple processes such as oxidation, many of which are of 
considerable therapeutic importance {e,g, cotarnine). 

In considering these alkaloids, it will be found that our 
knowledge of their constitution is far more satisfactory than 

1 Japp and Davidson. J. 0. S., 67 (1896), 1 ; Zincke and Hof, Ber,, 12 
(1879), 1644. 



ALKALOIDS: MORPHINE AND ISOQUINOLINE GROUPS 117 



that of the alkaloids of the morphine group. In the majority 
of cases, not only is the constitution known with a high degree 
of certainty, but in recent years it has, in many cases, been 
confirmed by the synthesis of the alkaloid. 

Of the alkaloids of this group found in opium, narcotine and 
papaverine are present in the largest quantities. The consti- 
tution of the latter has been determined chiefly by the work of 
Goldschmidt,^ which leaves no doubt that the structure of this 
alkaloid is represented by the formula — 

CH,0/'\/\ 



 I 
CH 



N 



2 



/\ 



V 

OGH 



OCH, 



t 



This has been oonfirmed by the brilliant synthesis of papaverine 
by Fictet of Geneva.* 



Piotet had already shown' that 
substances of the typ< 



OH, 



CH, 



on treatment with dehydrating 
agents, lose a mole- GHj 

oule of water, giving f'\/ \ 
dihydro - isoqnino- 
line derivatives of 

the type— \/\ /" 

OR 






H 



\ 
NH 

/ 
CO 

\ 
B 



OH 



1 



2 



1 Manatsh., 4, 714 ; 6, 372, 667, 954 ; 7, 485 ; 8, 510 ; 9, 42, 327, 849, 762, 
778; 10, 166, 673, 692; 13, 697; 17, 491 (1883-1896). 

> Piotet and Gans, Ber., 42 (1909), 2943 ; C. JR., 149 (1909), 210. 
* Piotet and Kay, Ber„ 42 (1909), 1973. 



Its 



SYNTHETIC DRVOS 



In this way he suooeeded in obtaining dihydro-papaverine ^ — 



CH,0 



CH,0- 



CH, 



CH, 



N 
C 



h 



^2 



/\ 



OCH, 

but this oannot be converted into papaverine by oxidation, as 
any attempt to do this leads to the disruption of the whole 
molecule. Papaverine could not be obtained directly by using 
(CH,0),C4H, . CH=CH . NH, instead of— 

(GHjOjjG^iHj . UUj . GEl2 • NHj 
at the beginning of the synthesis," as the former substance is 
too unstable for this purpose. The difficulty was finally over- 
come by preparing — 



CH— OH 



GH 
CH 0-<^\/ ^ 



CH,0 



^\/ \ 



CH,0 



CH, 



N 



C 
GH, 



/ 



NH 

\/\h / 

CO 



or 



CH, 



^\ 



\/ 



OCH 



s 



OCH 



OCH, 



3 



OCH 



I 



i Piotet and FinkeUtein, O. B., 148 (1909), 936. 



ALKALOIDS: MORPHINE AND ISOQUINOLINE GROUPS iig 

which on treatment with phosphorus pentoxide in xylene solu- 
tion loses two molecules of water with the formation of papaver- 
ine. The product thus obtained was in every way identical 
with papaverine obtained from opium. The first stages of the 
synthesis are concerned with the preparation of — 






CmOKJ I ' L JOCH3 




* ^ NHgHCl OCH3 

Hydrochloride o'l funino acetoveratrone. Homoveratroyl chloride. 

The first mentioned is prepared according to the following 
scheme : — 

CHgOyv CH3 . 00 . 01 in OS, CHgOyv 

CH30U « CHgoU-^CO— ^^3 

Veratrole. Aceto-veratrone. 

Amyl nitrite CHjO^ 



 :(^ 



+ sodium ethoxide CH^OS/— ^O" ^^==^— °^ 



3 

Isonitroso compound. 



Stannous chloride. 



CH3O 



(^ 



CH oKj—GO^-GR^—lHILz • HCl 

Aminoaceto-veratrone hydrochloride. 

The starting-point of the other half of the synthesis is vanillin — 

/OH 
CHO CHO . CH<; 

Methylated /\ /\ ^CN 



Methylated /\ /\ 

OCH3 ^ U0CH3 "w^ Uo 

OH OCH3 OCH3 

Vanillin- Veratraldehyde. 



CH3 



lao SYNTHETIC DRUGS ' 

CH(OH)— COOH CHj— COOH CHj— COOH 






Homopiotooste- Homoveratrio 

ohuio aoid. sold. 

This homOToratrio aoid, treated with PGlg, yields the chloride- 

CH,— GOCl 




>CH, 
K5H, 

This on shaking with — 

CHjO/V-CO— CH,— NH, . HCl 

CH,oU 
Amino-«oato-vatattone hydioohloride. 

in cold potash solution ^ves, by loss of HGl — 

CO 
^°p/ \CH,— NH— CO— CH,— <^OCH, 
CH,oU OCH, 

which by redaction with sodiam amalgam in alcohol yields- 

/OH 
CH^ 



.op./^^Y' 



CH,0|^ 
CH,0^^ 



CH.O^/ NH 

CO 




which on dehydration gives papaverine, as previonsly described. 
Papaverine has only a slight narcotic action, being inter- 
mediate in this respect between morphine and codeine.^ Ac- 
cording to Bernard,* the chief opinm alkaloids stand in the 

>Sohi6der, A. : P. P., 17 (1883), 96. 
'Barnard, O. B., 59 (1861), 406. 



ALKALOIDS: MORPHINE AND ISOQUINOLINE GROUPS 121 



following order in regard to their power of causing convulsions : 
thebaine, papaverine, narcotine, codeine, and morphine. Of 
these, thebaine is the only one producing strong tetanic con- 
vulsions. Of the alkaloids not mentioned in this list, laudano- 
sine and laudanine have this property strongly marked, the 
former being slightly less and the latter slightly more active 
than thebaine itself in this respect. 

Laudanosine closely resembles papaverine in its structure, 
being the methyl derivative of tetra-hydro*papaverine. 



CHg 



Ga 



CH30 



^^«°\/\/^- 



-ca 



CH 

I 

CHn 

A 



\^0CH3 

OCHj 

This was shown by Pictet and Athanescu,^ who obtained it by 
the reduction of the metho-chloride of papaverine with tin and 
hydrochloric acid, and resolution of the racemic compound thus 
obtained with quinic acid. The dextro-compound was found to 
be identical with laudanosine. It has also been obtained by 
the reduction of papaverine to tetrahydro-papave^ine, and 
methylation of the latter,^ but its complete synthesis, which 
has been recently accomplished by Pictet and Finkelstein,' is 
of greater interest. Dihydro-papaverine was synthesized by 
Pictet's general method for the preparation of this type of 
isoquinoline base (c/. previous pages), and the metho-chloride 
of this compound gave by reduction racemic laudanosine. 
which was then resolved as described above. This synthesis 
was carried out a short while before that of papaverine, and 
was therefore the first complete synthesis of an opium alkaloid. 

ijBar., 33 (1900), 2346; G, JR., 131 (1900), 689. 

«Pyman, J, C. 8., 95 (1909), 1610. 

s Pictet and Finkelstem, C. 12 , 148 (1909), 295. 



^22 



SYNTHETIC DRUGS 



NarcoUne and its decomposition products have provided 
material for an enormous number of researches. These are too 
numerous to be described here, but they point to the probability 
of the structure shown in the accompanying formula.' 

CHji 



CH,<^ 



0— 



CH< 



•\/\ N-CH3 
OH,0 \/ 
CH 



CH— O 
I 

OCH, 



Becently narcotine has been synthesized \ 

by Perkin and Bobinsoh,^ who combined 

ootamine and meoonine — 

CH, 

/\ 
/ \ 

.0-^\^ \CH 




CH, 






\/^\ 



CH 



OHi— N 



CO 



+ H 



— CH, O 
CH 



/ 



OCH, 



Gotarnine. 



Meconine. 



<Z>OCHj 



therqby obtaining racemic narcotine (gnoscopine), which was 
then resolved into its optically active constituents. Meconine 



^The positions of the methoxyl, (OGH3), and piperonyl, GH. 



/ 



o— 



'\o-' 

groups were doubtful, but have been finally established by Freund and 
Oppenheim. Ber., 42 (U909), 1084. 

3 Perkin and Robinson, Proc, Ohsm. Soc., 26 (1910), 46 and 181. 



ALKALOIDS: MORPHINE AND ISOQUINOLINE GROUPS 123 

was synthesized by Fritsoh^ in 1898, and the synthesiis of 
cotarnine has very recently been accomplished by Sal way ,^ so 
that the synthesis of narcotine is now complete. ' 

The physiological action of narcotine is similar to that of 
morphine, but less intense. Chemically it is closely related 
to hydrastine, the alkaloid to which the physiological action of 
Hydrastis canadensis is chiefly due. This latter alkaloid, which 
is an astringent and styptic, is used in uterine haBmorrhage, etc. 
It was first isolated in a pure condition by Perrins in 1862,^ 
and the first observations bearing on its structure were made 
by Power ^ in 1884. Since then the numerous investigations 
of Freund and of Schmidt have fully established the structure 
of this alkaloid. They have shown that it is represented by 
the formula — 

OH,/ I 

\0-^ j\ /N-CH, 



A 



H— O 

0CH3 

which only differs from that of narcotine by the absence of one 
methoxy group. 

The alkaloid present in largest quantities in hydrastis is 
berberine, but its physiological action is not very marked, and 
hence it does not play so important a part as hydrastine. It 
is also found in a large number of other plants, and was first 
discovered in 1826 in the bark of the prickly ash.^ It has the 
formula C20H17N64 + HgO, and the work of W. H. Perkin, jun., 
and others indicates that the probable formula of the substance 
is as shown.* 

1 Fritsch, AnnaUn, 301 (1898), 861. 

«Salway, J. C.S.^VI (1910), 1208. 

' PhoarmaceviicaL Journal [2], 3 (1862), 646. 

* Ibid. [8], 15 (1884). 297. 

<* Ghevalier and Pelletan, Journal de Ghirme MedicaU, 2 (1826), 314. 

^ Perkin and Bobinson, J. C. S^, 97- (1910), 306. 



124 



SYNTHETIC DRUGS 



^<o 



0— 



I 



II 
HO 



N— OH 



H 



^\ 



H^/OCH, 

OCH, 
Berberine. 

This is related to that of hydrastine and narootine, and 
is still more olosely related to that of oorydaline, the chief 
alkaloid in CorydaUs cava. Corydaline was discovered in 1826 
by Wackenroder,^ and the formula shown herewith was sug- 
gested for it by Dobbie and Lauder.* 



CH,0 
CH,0 



^\/^°«\CH 



2 







CH— CH. 



An alkaloid which may be regarded as an isoqninoline de- 
rivative, although it does not actually contain the isoquinoline 
ring, is narceine. It is found in opium, but does not have a 
well-marked physiological action. It can be obtained from 
narcotine by heating the metho-chloride of the latter with alkali. 

CaaHjgOyN.CHaCl + NaOH - NaCl + CajHj^OgN. 



^ Berg. Jahresh,, 7 (1626), 220. 



*/. O. 5.,83(1903), 605. 



ALKALOIDS: MORPHINE AND ISOQUINOLINE GROUPS 125 
This fact led Freund and Frankforter ^ to suggest the formula — 



CH,0 V^2 



a 



io 



I COOH 

I 11 
\/OCH, 

OCH, 

for naroeine, which indicates that it is formed from narcotine 
by the rapture of both the lactone and the pyridine rings. 

One of the most important "artificial alkaloids" that are 
obtained from the true alkaloids of the isoqninoline series is 
ootarnine. It was first obtained, together with opianic acid, by 
Wohler ^ in 1844, by the oxidation of narcotine with manganese 
dioxide and sulphuric acid. This substance resembles naroeine 
in the fact that in the free base the pyridine ring is opened out, 
but in the salts which are formed with elimination of water, the 
ring closes and derivatives of di-hydro-isoquinoline are formed. 

CH, 

I + HCl 

^ .. NH— CH, 



^O— 



CH,0 CHO Qg 

.0-^\/ \CH 



'\ 



2 

+ H,0 
^^^z CH CI 



3 



There is some evidence that the free base also exists as an 
isoquinoline derivative of this quaternary ammonium form 
when dissolved in alcohol.' This alkaloid is of importance in 
medicine as a styptic and as a uterine sedative, and has been 

* Annalm, 277 (1893), 20. « Ibid,, 50 (1844), 1. 

' Dobbie, Lauder, and Tinkler, J. C. /S., 83 (1908), 598. 



laS 



SYNTHETIC DRUOS 



brought into the market aader the name of " Stypticine," and 
its phtfaalio acid salt under the name of " Styptol." 

Hydrastine, on oxidation with MnOj and HjSO^, behaves id 
a '^ery similar way to narcotine, yielding opianic acid and a 
basic substance,' AyirosttniiM, whfch corresponds to cotcumine — 

CHO 



./\ 



+ H,0 + 0/ 



■COOH 



OCH, 



OCH, 



/OH 



CH, 
./\/ \ 



\/ 



CH, 

1 
NH 



CHO 



CH, 

Physi<dogically, hydrastinine ° resembles 'cotarnine very 
closely. 

It has been shown by Pyman,^ that laudanosine, on otsidation 
with MaO^ and HjgSO^, behaves in a precisely-similar way to 
narootine and'hydrastine. The products are a basic substance, 
4-5 dimethoxy-2 /8 methj^aminoethyl-benzaldehyde, and vera- 
traldehyde, the former being analogous to cotarnine and 
hydrastinine, and the latter corresponding to opianic acid. 

CH, 



CH,0 



^\/ \ 



CH,0 



CHj 

L 



+ 20 



^H. 



CH 



CH.— ^ 



OCH, 



=/ 



OCH, 



CH, 
CH,0^\/ \ 



CH,0 



%/ 



CH. 



N— CH, 



CHO 
+ OHC— 



^ 



OCH, 
]^OCH, 



1 Pyman, J. C. S., 96 (1909), 1266. 



ALKALOIDS: MORPHINE AND ISOQUINOLINE GROUPS i%| 

The former combines with acids to^form ssjts of thp isom^r^q 
iso-quinolinium hydroxide, in just the same way a^ do cotarnine 
and hydrastinine. ' , 

Of these, the chloride, which is 6-7 dimethoxy-2 methyl- 
3-4-dihydro-isoquinoliniiim chloride, has. be^ introduced into 
practice under the name ** Lodal " — ^ 

CH, 



CH,0^\/ \ g. 



8' 



2 



N— CH, 



CH CI 

It causes a. rise of blood pressure, and renders the boart-beat 
slower and stronger. 

Other pressor substances, which . jiiave been, x^btftined from 
iaoquinollAC alkaloids will be considered in .the next chapter. < 

It is of interest to npte that tjie N-jn^tl;Lyl .diiriYAtiiy^si .of 
tetrahydrojrjsoquinoline (narcotjne, lapd^inosine, and l^ydi:a3liine) . 
are convulsant poisons, wjiile those derived from dihydro-i^p- , 
quinoline (cotarnine, "Lodal," and hydrastinine) are. not. . ^his 
relation does not hold for those derivatives, such as papaverine, 
which contain no methyl group attached to the nitrogen. 

More recently it has been shown ^ that emetine, C29H40O4N2, 
and cephaeline, GgsHjgO^Ng, the chief alkaloids of ipecacuanha, 
are derivatives of isoquinoline, as the former on oxidation gives 
6-7-dimethoxyisoquinoline-l carboxylic acid, 

COOH 

which is also an oxidation product of papaverine. It was also 
shown that emetine is the monomethyl ether of cephaeline, the 
former being C25H23N2(OCH3)4, and the latter, 

C25H23N2(OH)(OCH3)3. 

These alkaloids have attracted considerable attention recently 

1 Wellcome and Pyman, English Patent (1909), 814. 
2Carr and Pyman, J. C. S., 105 (1914), 1591. 



128 SYNTHETIC DRUGS 

owing to the valuable effect of emetine hydrochloride in the 
treatment of amoebic dysentery. It appears to have a specific 
effect on the protozoal parasites just as quinine has on those of 
malaria. 

According to Pyman,^ the protozoacidal effects on this para- 
site (Entamaba hi$tolyUca) of emetine, cephaeline, N-methyl- 
emetine, and N-methyl-cephaeline are practically equal. Various 
other interesting facts concerning the relation between chemical 
constitution and physiological action in this field are given in 
the same paper. 

In some cases the use of the double iodide of emetine and 
bismuth has been found to be more advantageous than that of 
emetine hydrochloride itself. 

Becently two more alkaloids have had their constitution 
established by Perkin,^ and shown to be isoquinoline derivatives. 
These are cr3rptopine and protopine, both of them occurring in 
very small quantities in opium; the latter is also obtainable 
from many-«ther plant sources. 

» Pyman, /. C. S., Ul (1917), 1127. » /. C. S., 109 (1916), 815. 



CHAPTBE IX. 

ADRENALINE AND OTHER DERIVATIVES OF ETHYLAMINE. 

Within recent years, a large number of ethylamine derivatives, 
possessing powerful physiological action, have been isolated from 
various plant and animal sources. Many of these are derivatives 

of para-hydroxyphenylethylamine, HO^^^CHj, — CHg — NHj, 
and have the property of producing effects very similar to those 
produced by stimulation of the sympathetic nervous system,^ 
one of the most notable of these being rise of blood pressure. 
Para-hydroxyphenylethylamine is present in aqueous extracts 
of ergot, and other closely related substances are also found in 
various plants, but the most important compound of this class 

is adrenaline, HO<^~)CH(OH)— CHg— NH— CH3, an active 

principle which has been isolated from the suprarenal glands. 
It was first obtained in the impure condition by Abel and 
Crawford, in 1897,^ and in a more pure condition as the benzoyl 
derivative by Abel, in 1899.^ It was called epinephrine by 
these investigators, and 1^ was also isolated by von Fiirth,^ who 
gave it the name suprarenine. The name adrenaline was first 
given to it by Takamine,^ who was also the first to obtain it 
in a crystalline condition. He proposed the.formula G1QH13O2N 
from the results of his analyses, and also made the first observa- 
tions throwing some light on its constitution, as he obtained 

^ 'larger and Dale suggest the term *' sympathomimetio " to describe 
this action. 

^ZeU. physiol. Chem,, 28 (1896), 818. 

*Amer, Joum, of Physiol., 3 (1900), zvii.-xyiii. ; Proc. of Ameir, Physiol, 
80c, (1898), 3. 

« Von Furth, Zeit, physiol Chem., 29 (1900), 105. 

*Takamine, Amer, Joum, Phann.^ 73 (1901), 523; Proc. Phynol. 80c, 
(1901), zziz..zxz. ; D. B. P., 131,496. 

X29 9 



* 



X30 SYNTHETIC DRUGS 

substanoes from it supposed to be catechol and protocatechuio 
aioid. andHO<' ^COOH. 



^a 



Shortly afterwards it was isolated by Aldrich by means of 
a somewhat different method, and he gave to it the fc^rmula 
CgHjgOgN, which is now universally accepted. Abel still pre- 
ferred the formula G^oH^OiNy^HsO, whioh corresponds to 
almost identically the same composition as GgH^gOgN, but he 
brought forward no evidence to show that it contained wate^ 
of crystallization. Pauly^ confirmed the formula G,HigO(N, 
and suggested that it contained the groupings — 
H H 

— C— CH,— NH— OH, or — n/ 



A: 



ffl . ->, CHi— OH 

Von Fiirth^ had already suggested the formula (H0)3Cen,- 
[C2H,(0H)NH— CHJ, as he had found that it did not con- 
tain a methoxy group, and that it yielded methylamine salts 
on treatment with concentrated acids. Jowett' confirmed 
the formula GJBi^fi^l^y and from the products of a potash 
fusion isolated a small quantity of a substance believed to be 
protocatechuio acid, but obtained more positive evidence by 
methylation and subsequent oxidation, by which means veratric 

OCH3 

/NOCfHo 
acid, I I , was obtained, and he therefore suggested the 

COOH 
alternative formulae — 

OH 
r^OH 




I 




OH CHj . H--C— NH— CHg 

I I • 

CH2— NH— CH, HO— CH— NH— CH3 CH2— OH 

I. n. m. 

1 Pauly, Ber., 36 (1903), 2944. 

» Von Purth, Beitr. Chsm. Physiol. Path., 1-(1901), 248, 

> Jowetfc, J. O. 8., 85 (1904), 192. 



ADRENALINE AND DERIVATIVES OF ETHYLAMINE 131 

with a preference in favour 6t I., which is the formula at present 
accepted as representing ther constitution of adrenaline. 
' In 1904 Friedmann ^ showed that the benzenesulphonyl de- 
rivative of adrenaline on oxidation yielded the corresponding 
derivative of a ketone adrenalone, which he also obtained by 
the action of methylamine on chloracetyl-catechol — 

H0< \_00— CHj— CI, 

and which, therefore, has the constitution — 

H0/~y-<30— CHj— NH— CH3. 
HO 
and this confirms Jowett'd formula for adrenaline. 

From this time onwards, the chemical investigations of 
adrenaline have had as their chief object the synthesis of 
this important and valuable substance. The adrenalone of 
Friedmann can be obtained by the action of an excess of 
methylamine on chloracetyl-catechol, the resultant base being 
precipitated by ammonia.^ 

OH OH 

OOH Ol.OO.OHjCl AOH H— NH-OH3 

Ghloracetyl-chloride. \/ . Mebhylamine. 
Catechol. | 

CO— CH2— 01 

Ohloraoetyl-catechol. 

OH 
sOH 




CO— CHg— NH— CH3 

Methylamino-aoetO'Catechol 
(adrenalone). 

The reduction of this ketone to the corresponding secondary 
alcohol (adrenaline) presented great difficulty, but it was suc- 
cessfully accomplished by electrolytic reduction or by the 
action of aluminium amalgam on the sparingly soluble sul- 
phate of the ketonic base.^ 

1 BeUr. Chem, Phyaiol. imd PatTuAogie, 6 (1904), 92. 
a Stolz, Ber., 37 (1904), 4149 ; D. B. P., 162,814 ; English Patent (1908), 
25,480; Dakin, Proc, Bay. 80c., 76. B (1905), 491. 
* D. B. P., 157,300 r also Dakin, lac, cU, 

9* 



132 SYNTHETIC DRUGS 





O— CHj— NH— CH, H— C(OH)— CH,— NH— OH, 

Another method for the synthesis of adrenaline starts from 
protocateohuio aldehyde. This on treatment with hydrocyanic 
acid yields the cyanhydrin, which is then reduced to an amine 
which can be converted to adrenaline by methylation. This 
method is not used commercially. 

> HO/ — S— CH(OH)— CN 




2^—^ HON H^r^ 



► H0<^ >— CH(OH)— CHa— NH^ 

HO 

^°<CZ>~^^(^^)~^^2— NH— CH, 

The product thus obtained is the racemic form of adrenaline, 
which is less active than the naturally occurring l8Bvo-rotat(»ry 
variety. 

The resolution of racemic adrenaline into its two optically 
active components has been accomplished by means of the 
fractional precipitation of its salts with tartaric acid, and also 
by means of PenicUlium glaucum} The synthesis of natural 
adrenaline is therefore complete. 

The methylene and dimethyl ethers of adrenaline have been 
synthesized by means of a different method,^ but unfortunately 
these could not be transformed into .adrenaline itself. 



O 



■> 



OH,— Mg— 1 




CHO 

Piperonal 



1 Flacher, ZeiU physki, Chem,, 58 (1908), 185, 189 ; and also Meister, 
Lucius, and Brdning, D. B. P:, 222,451. 
s Bargerand Jowett, J, C. S., 87 (1905), 967. 



ADRENALINE AND DERIVATIVES OF ETHYLAMINE 133 



heating 




V y methylamine v y 

CH(OH)— CHaBr CH{OH)— CH2— NH— CH, 

The methylene ether of adrenaline thus formed has a physio- 
logical action similar to that of adrenaline itself. Similarly 

OCH3 

veratraldehyde, [ | ^' was transformed into the dimethyl- 

CHO 

OCEL 

ether - of adrenaline, f | "^ , although 




;H(0H)— CH,— NH— CH, 
this was only obtained as a syrup. Although by the action of 
phosphorus pentachloride on the methylene ether, Barger and 
Jowett {loc. dt.) were unable to obtain a chlorinated com- 
pound which should yield the dihydroxy-compound with water — 

o— ca 




^2 




)H(OH)— CHgBr 
Bottcher^ states that an excess of phosphorus pentachloride 

1 Bottcher, Ber., 42 (1909), 258. 



134 SYNTHETIC DRUGS 

OH 

/\0H 
gives I J , which with aqueous methylamine 

CH(OH)— CHaBr 
yields a physiologically active base, supposed to be adrenaline. 
Pauly,^ however, considers that Bottcher has not proved the 
formation of adrenaline by this method. 

Considerable light has been thrown on this reaction by 
Mannich,^ who showed that a mere direct replacement of the 
halogen by the methylamino group does not take place in chlor- 
or bromhydrins of the types — 

CHa^ \CeH3— CH(OH)— CH^Br 

and (CH30)3C5H3— CH(OH)— CHjBr. Under the influence of 
methylamine, hydrobromic or hydrochloric acid is lost, result- 
ing in the formation of an unstable oxide of the type — 

{CRfi)^C^^ — CH — CHj, 

which then reacts with more methylamine to form bases of 
the adrenaline series, e,g. — 

.OH 
(CHjOAHs— CH/ 

^CHjj— NH— CH3 

or of the i^oadrenaline series, e,g, — 

/NH— CH3 
(CH30)AH3-CH<; 

^CHa— OH 

Mannich and Jacobsohn ' succeeded in preparing the methyl- 
ene and dimethyl ethers of adrenaline in a pure state, and 
they also obtained the methyl ether of ^-methyl-adrenaline by 
the action of bromine on methyl-isoeugenole. 

1 Pauly, B^r,, 42 (1909), 484. 

3 Mannich, Arch. P^rm.,. 248 (1910), 127. 

' Mannich and Jacobsohn, Apothek, Zeitg,, 24 (1909), 60. 



ADRENALINE AND DERIVATIVES OF ETHYLAMINE 135 



CH,0^ :>— CH=OH— CH 






3 



CH, 



. > CH,0<f3^HBr— CHBr— CH, 

CH,C) 

* GRjdj >— CH(OH)— CHBr— CHj, 

CHjO^ 

CH, 




*. CH,0< >— CH(OH)— CH— NH— CH, 



CH, 
This then gives jS-methyl-adrenaline — 

HO<ri>CH(OH)— CH— NH— CH, 

on treatment with hydriodic aoid. According to Kobert this 
substance has not the physiological action of adrenaline. 

Meanwhile an extended physiological investigation of ad- 
renaline was carried out by Elliott/ who confirmed and ex- 
tended the earlier work which Schafer and Oliver, and Langley 
had carried out with extracts of the gland. In general, the 
effect of adrenaline on any structure is similar to that which 
follows excitation of the sympathetic nerves supplying the 
tissue. If administered subcutaneously or locally to mucous 
surfaces, it causes very marked constriction of the blood-vessels, 
and so arrests bleeding. In moderate doses, subcutaneous in- 
jections produce no general systemic effect, very much larger 
doses being needed to raise the blood pressure by this means. 

It is of interest to note that there is a very marked differ- 
ence in the physiological activity of the naturally occurring 
IsQvo-adrenaline and the dextro isomeride, this being one of 
the very best examples of difference in physiological behaviour 
between stereo-isomerides. It was shown by Cushny^ that 
natural IsBvo-adrenaline acts approximately twice as strongly 
in increasing the blood pressure as synthetic racemic-adrena- 
line, and presumably also on the other organs affected by 
adrenaline. From this it was inferred that d-adrenaline was 

1 EUiott, Jowm. ofPhyiiol, 32 (1905),401. 
s Gushny, Joum. of Physiol,, 37 (190»), 190. 



136 SYNTHETIC DRUGS 

inaotive on these tissues, and this view was apparently con* 
firmed by an examination of partly isolated (^-adrenaline. The 
general character of. these results was confirmed by other 
workers,^ but subsequently Gushny ^ showed that (i-adrenaline 
is not quite inert in this respect, but has an activity about 
one-twelfth of that of Z-adrenaline, so that the action of r- 
adrenaline is almost entirely due to the Z-adrenaline contained 
in it. 

The synthetic racemic mixture can be completely converted 
into the desired active component. Either the dextro or the 
IsBvo compound can be racemized by treatment with acids ; the 
inactive mixture is then resolved into its components, and 
the isomeride not required can then be again racemized and 
subsequently resolved, this process being repeated as often as 
r^quired.^. The authors of this method state that the dextro 
compound also possesses valuable therapeutic properties. 

The therapeutic uses of adrenaline are very numerous, and 
a mere list of the references to the literature of this subject 
would fill pages; an account of many of these publications 
is giv«n in Merck's Eeports during the last fifteen years. 
Adrenaline is largely used in conjunction with cocaine and 
eucaine, as it produces a localized ansamia, and so checks bleed- 
ing, and it also appears to neutralize the toxic effect of cocaine. 
The action of adrenaline in producing ischsemia finds applica- 
tion in a variety of complaints, hay-fever being an example. 

Adrenaline is also met with under the names of hemisine, 
adrenine, epinephrine, suprarenine, etc. 

Becently various substances chemically related to adrena- 
line, and to a large extent resembling it in their physiological 
action, have been isolated from various plant and animal 
sources. Of these, para-hydroxyphenylethylamine, 



H0< >— CH,r-CH,— NH, 

which may be regarded as the mother substance of the series, 
is the most important. It was first prepared in small quantities 

1 Abderhalden and MuUer, ZeU. phywol. Chem., 68 (1908)< 185 ; Abder- 
halden and Thies, Zeit. phyaioL Chem,, 59 (1909), 22 ; Abderhalden and 
Slavy, ZeiL physiol Chem., 66 (1909), 129. 

« Cushny, Joum. of Physiol., 38 (1909), 269. ' D. R. P., 220,366. 



ADRENALINE AND DERIVATIVES OP ETUYLAMINE 137 
by lieating tyrosine,i H0< >CH^— CH— COOH, and it has 

since been obtained in small quantities from various animal 
sources. Putrid meat has for some time been known to pro- 
duce a rise of blood pressure (pressor action), and in 1909 it 
was found that this action was due to a number of amines,^ of 
which para-hydroxyphenylethylamine had the most powerful 
action. The amines which showed this action in a weaker 
degree were iso-amylamine, (CHg)2CH — CHg — CHg — NHg, and 
phenylethylamine. It is almost certain that these bases are 
produced in the process of putrefaction by loss of carbon 
dioxide from the corresponding amino acids : — 



Para-hydroxyphenylethylamine, H0\ /CHg — CHg — NHjj, 

^COOH ^ 
from tyrosine, HCX^^^CHn— CH( . 

Phenylethylamine, CgHg — CHg — CHg — NHg* from phenyl- 

/COOH 
alanine, CeH.— CHg—^CH^ 

^NHg 

And isoamylamine, (CH3)2CH — CHg — CHg — Nfig, from 

/COOH 
leucine; (CH3)g— CH— CHj— CH<f . 

^NHg 

Putrid placental extracts had also been shown toprod^uce a 
pressor action,^ and para-hydroxyphenylethylamine has b^en 
isolated from such extracts.^ 

The drug ergot has long been used on account of its th^a- 
peutic properties, but it is very variable in its activity, s^d 
requires to be physiologically standardized owing to the un- 
satisfactory state of our knowledge of the alkaloids present 
in ergot. Becently, however, a great deal of light has been 
thrown on the chemistry of ergot by the work of Barger, 

^ Schmidt and Nasse, Annalen, 133 (1865), 214. 

^Bazger and Walpole, Joe^m. of .Physiol, 38 (1909), 848; Dale and 
Dixon, ibid., 39 (1909), 25. 

•Dixon and Taylor, B. M. J., II. (1907), 1160. 
* Rosenheim, Joum. of Physiol., 38 (1909), 337. 



138 SYNTHETIC DRVOS 

Dale, and others. The amorphous alkaloid ergotoxine ^ id 
physiologically active, hut it does not possess all the character- 
istics of the action of ergot, and the small amount of this 
alkaloid present in most pharmacopoeial preparations of ergot 
led to the postulation of an active principle soluble in water.^ 
The physiological properties of para-hydroxyphenylethylamine 
suggested that it might be the expected active principle, and 
this expectation was realized when it was shown to be present 
in aqueous extracts of ergot,' and to be the chief cause of their 
physiological action. Not only has this substance been isolated 
from ergot,^ but synthetic methods for its preparation have 
been devised which have rendered practicable its introduction 
into therapeutics. These syntheses will be discussed together 
with those of other compounds of this series, but mention 
should be made at this point of another base isolated from 
ergot.' This is j^^minazolyl-ethylamine — 



NH— CH. 

I >C— CHj— CH«— NH, 

OH=N/ 



^2" 



and it is formed from the anuno-acid, histidine — 

NH— CH. 



NHj 



CH=N/^ 



^C— CHo— CH— COOH 



by loss of carbon dioxide in just the same way as p.-hydroxy- 
phenylethylamine is formed from tyrosine. The action of 
ergot in producing gangrene of the cock's comb is regarded ^ as 
being due to the alkaloid ergotoxine, and the rise in blood 
pressure is attributed to p.-hydroxyphenylethylamine, while 
the powerful action of ergot in stimulating the isolated uterus 
to tonic contraction is caused by ft iminazolyl-ethylamine. 
This substance, although it has a very powerful physiological 
action, differs from all the other active derivatives of ethyl- 

^Barger and Garr, J. C, fif., 91 (1907), 357. 
> Barger and Dale, Bio-Chemical Journal, 2 (1907), 286. 
s Ibid., Proc. Physiol Soc., 15th May, 1909. 
« Barger, J. C. 8., 95 (1909)j 11S3 ; Skiglish Patent (1909), 814. 
B Barger and Dale, Proc. Chem. Soc., 26 (1910), 128 ; J.C.8.,^ (1910), 
2592. 

« ibid., Proc. Physiol, Soc, 1st July, 1910, xzzviii. 



ADRENALINE AND DERIVATIVES OF ETHYLAMINE 13O 

amine described in this chapter in causing a lowering instead 
of a rise of blood pressure. 

It has been introduced into medicine under the names of 
Histamine and Ergamine, 

The original method for the synthesis of p.-hydroxy- 
phenylethylamine was by the reduction of p.-hydroxyphenyl- 

acetonitrile,^ HO ^^ X ^H^ — CN, and subsequently two other 
methods of synthesis were described.^ One of these is by the 
nitration of benzoyl-phenylethylamine, reduction of the result- 
ing para-nitrQ compound to the amine, which yields the ben- 
zoyl derivative of the desired product when diazotized in 
boiling solution. This benzoyl derivative is then hydrolyzed. 

<CI]>CH2— CH2— NH— COCeHg 

► N02<3CH2— CHji— NH— COC^Hfi 

-> NH2OH2-(3H2-NH--C0CeH, 

HNOj 

H0<CI>CH2— CH2— NH— COCflHfi 

HO<~>CH,— OH,— NH, < 

The other method starts from anisic aldehyde, CH^tC K X ^HO, 
which, by the method of Ferkin and Bobinson,' yields the acid, 

CHaO<""^>CH«>— CHa— COOH. This is then converted into 
the chloride, and thence into the amide — 

CH,0<r~>CH,— CH,— CO— Nti,, 

which by the Hofmann reaction is made to yield the amine 

CHaO<r^>CH«,— CH^— NH^. By means of strong hydro- 
bromio acid, the methoxy group is converted into hydroxy, 
giving para-hydroxyphenylethylamine. 

p.-Hydroxyphenylethylamine has also been prepared from 
anisaldehyde by Bosenmund,^ who condensed the latter sub- 
stance with nitromethane to prepare )3-nitro-p.-methoxystyrene. 
This is then reduced to p.-methoxyphenylethylamine, which is 
demethylated with hydriodic acid. 

1 Barger, J. 0^8., 95 (1909), 112S ; English Patent (1909), 814. 
> Burger and Walpole, J, C. 8., 95 (1909)1 1720 ; English Patent (1909), 
1661. 

s Perldn and Bobinson, /. C. 8., 91 (1907), 1079. 
« Bosenmund, Bar., 42 (1909), 4778. 



140 SYNTHETIC DRUGS 



CH30< >CH(p + HgjCH— NO2 =» CH30< X5H=CH— NOg 

I 
CH,0< >CH,— CH,— NH, 

H0<_^H2— CH2— NH2 

This substance has been introduced into practice under the 
name of '' Tyr amine *' as the chief active pressor principle of 
a^eous extracts of ergot, and being a pure chemical compound 
it has the advantage in being certain and uniform in its 
action. 

Tyr&mine and adrenaline are representatives of two im- 
portant subdivisions of these pressor amines, the former being 
the simplest member of those derivatives of phenylethylamine 
containing one phenolic hydroxyl group in the para position 
to the ethylamine group, and the latter being a representative 
of the compounds containing two phenolic hydroxyl groups in 
the 3-4 position. Many other compounds of this type have 
been obtained by synthetic methods, and their physiological 
action determined. The syntheses of some of the most im- 
portant will now be considered, and the physiological action 
dealt with subsequently. 

The simplest member of the adrenaline series {i.e. those with 
two phenolic hydroxyl groups in the 3-4 position) is 3-4 di- 

OCH3 OCH3 

0OCH3 AOCH3 
. NHjOH 

CH2 

I CH=NOH 

CHO 



OCH, 





Sodium amalgam t HI 





I 



ADRENALINE AND DERIVATIVES OF ETHYLAMINE 141 

hydroxyphenylethylamine, HQ<^ ^CEU— CHa— NHq. TJufil 

HO 
compound has been synthesized ^ from eugenol methyl ether, 
which by oxidation with ozone in benzene solution in pre- 
sence of water gives the aldehyde of homoveratric acid. This 
is converted into the oxime, which on reduction with sodium 
amalgam and glacial acetic acid yields the dimethyl ethpr of 
the desired compound. This ether is then converted into the 
dihydroxy compound with hydriodic acid in the usual manner. 
By the reduction of the oximes of other aldehydes and 
ketones, other members of these two series may be obtaioed. 
For example, homoanisic aldehyde, GKfi (^ ^ H^-t-^HO, 
gives p.-hydroxyphenylethylamine ; and para-methoxybenzyl- 
methyl-ketone, CHgO ^ X ^Hg — CO — CH3, gives, when treated 
in the same way, p.-hydroxyphenyl-isopropylamine— 

' tJH, 



HO<CI>--CH2-hOH— NH 



3-4 dihydroxyphenylethylamine (A) differs from adrenaline 
by the absence of a methyl group attached to the nitrogen and of 
an aliphatic hydroxyl group on the side Cham. An interesting 
intermediate compound between these two is 3-4 dihydroxy- 
phenylethylmethylamine (B). 

OH 
>H 






This, it will be observed, differs from adrenaline only by 
the absence of the aliphatic hydroxyl group, and it is of interest 
in being a connecting link between that substance and the 
pressor derivatives obtained from isoquinoline alkaloids {e,g, 
** Lodal" cf, previous chapter). It differs very little from 

1 Mannich and Jacobsohn, Ber., 43 (IdlO), 189. 



142 



SYNTHETIC DRUGS 



adrenaline in the qualitative nature of its physiological action, 
but the rise of blood pressure, although not so intense, is 
more prolonged. This substance has been introduced into 
therapeutics under the name of ** Epinine" It was obtained 
from l-keto-6-7 dimethoxy-2 methyl-tetrahydroisoquinoline ^ 
by heating it with hydrochloric acid at 170-175''. The reaction 
probably takes place in the following stages : — 



CH 



2 



OH,0/'\/'\oH, 



CH,0 



A-. 



CH 



»' 



00 



8 



CH, 



H 



HO 



o/^/N 



CO 



CH, 

N— CH, 



o/\/'\ 



HO 



CH, 



HO 



CH, 



NH 
CO CH, 



HO 



CH 



i 



NH 



\/\ 



k 



A 



Hc^, 



H 



HO 



i.e. H0<[3— 0^2— CHa— NH— CH3 

The corresponding propyl and ethyl derivatives were pre- 
pared in a precisely similar fashion. 

The other derivatives of 3-4 dihydrox3^henylethylamine 
to be considered, are mostly prepared by the same method as 
that used for preparing the ketone adrenalone and adrenaline 
itself. In that method, which has been already described, the 
methylamine used in the last stage of the synthesis of adrena- 
lone may be replaced by other amines or by ammonia. In this 
way Dakin ^ and Stolz ^ obtained the ketone — 

HO 
HO<C]>~CO— CH,— NH, 



1 Pyman.V. C. 5., 97 (1910), 264. 



^Loc, cit 



ADRENALINE AND DERIVATIVES OF ETHYLAMINE 143 

and its reduction product — 

HO 
HO<II>CH— OHa— NHa 

OH 

and also the substituted ketones of the type — 

(HO)2CeH8 . CO . CHg . NRiRj,. 
Before considering the physiological action of these substances 
with two phenolic hydroxyl groups, attention must be given 
to those synthetic products containing one phenolic hydroxyl 
group in the para position {Le. those related to tyramine). 
Most of the compounds of this type resemble tyramine in being 
derivatives of phenylethylamine, C^Hg — CHj — CH^ — NH2, 
rather than of phenylethanolamine, 

CgHg— CH(OH)— CHa— NHj , 
but one member of the latter class, and also the correspond' 
ing ketone, have been prepared and physiologically examined. 
These are p.-hydroxyphenylethanolamine — 

HO<[I>OH(OH)— CHa— NHg, 

and p.-hydroxy-w-amino-acetophenone — 

HO<I>-CO— CHa— NHa, 

which could not be prepared by the method employed in the 
adrenaline series by using phenol instead of catechol, but which 
have been prepared instead by the following synthesis^ (see 
next page). 

p.-Hydroxy-(i>-chloro-acetophenone could not be condensed 
with ammonia, bu{ its acetate could be condensed with potas- 
sium phthalimide, and the resultant compound, on removal of 
the phthalic acid by hydrolysis, yields the desired compound. 

The ketone then gives the corresponding secondary alcohol, 

H0< >CH(OH)— CHa— NH„ by reduction with sodium and 
alcohol. 

The other compounds of this series which have been physio- 
logically examined differ from tyramine only in having one or 
more of the hydrogen atoms of the amine group replaced by 
alkyl groups. 

1 Tatin, Gaton, and Hann, J, C. S., 95 (1909), 2113. 



144 SYNTHETIC DRVOS 

OCH, 





+ 01 

io 



aluminium 
chloride 




HjCl 

Aniflole + ohloraoetyl chloride. p.-h7droxy-»-chloro-aoetopheiione 

I Acetic 

I anhydride. 

O.CO.CHg 





GHjCl 




OH, . CO . ori>-CO— OH,— N I I 

\co/^/ 

hydrolysiE 




> JiO<^ V-CO— CHo— NH. 



with HOI ^ ^ -- - 2 2 



Of these, hordmine, HO^^^^^Ha— CHj— N(CH,)2, is an 
alkaloid, first obtained from barley germs,^ bnt it cannot be 
obtained from tyramine by methylation, as on attempting to do 
this, no compound but the completely methylated qnatematy 
substance, hordenine-methiodide — 

HO . OgH^ . CHj— OHj . N(CH3)4, 
could be isolated.^ A fortiori this method of direct methylation 
is inapplicable to the preparation of p.-hydroxyphenylethyl- 

1 L^er, C. B., 142 (1906), 103 ; 143> 234, 916. 
'Barger, J, C. $., 95 (1909), 219S. 



ADRENALINE AND DERIVATIVES OF ETHYLAMINE 145 

methylamine, HO . CgH^ . CHj— CH,— NH . CHj. Both these 
compounds have, however, been prepared by synthetic methods. 
The synthesis of hordenine was first accomplished according 
to the following scheme, which is self-explanatory : — ^ 

CgHg — GSL — GH2 — OH — >• CgHg — CS2 — CHj — CI 

PhenyWW aJoohol POl.  ^ . N(OHJ, 

CeH^— CHa— CHj— N(CH,)2 
HNO, 

N02<Z>CH,-CH2-N(CH3)2 

I Sn + HOI 



NH,--.<[_>--CH2— CHj— N(CH,)2 

I HNOa 

H0-<3-CH,-C52-N(CH,)2 

Very shortly afterwards, Eosenmund ^ obtained hordenine by 
the direct methylation of p.-methoxyphenylethylamine with 
alcoholic potash and methyl iodide, and separation of the 
primary, secondary, tertiary, and quaternary compounds thus 
obtained. The methoxy group is then converted into hydroxyl 
with hydriodic acid. Hordenine was also obtained by this 
investigator by the action of hydriodic acid on p.-methoxy- 
phenyl-trimethylammonium iodide — 

CH30<CI>CH2— OH,— N(CH,)8l 

> H0<~>-CH2— CH2— N(CH3)2 



Hordenine is manufactured by the methylation of p. -hydroxy- 
phenylethylamine with methyl chloride (CH3GI). 
The p.-hydroxyphenylethylmethylamine — 

H0<CZ>CH,-rOH2— NH— CHj 
and p.-hydroxyphenylethylethylamina — 

HO<CI>CH«— CH,— NH— CA 

were prepared by the methylation and ethylation respectively 
of the acetyl or benzene-sulphonyl derivatives of p.-methoxy- 
phenylethylamine, the former by both methods, the latter only 

^ Barger, J. C. 8., 95 (ld09), 2193. 
> Bosenmnnd, B0r., 43 (1910), 306. 

^ 10 



A 



HOI 



H3 



146 SYNTHETIC DRUGS 

by means of the benzene-sulphonyl derivatives.^ p.-Methoxy- 
phenylethylamine is prepared as indicated on pages 140-141, 
and the rest of the synthesis is easily understood from the 
accompanying scheme : — 

CH30<^]3CHj— CHj— NHj -> (acetic anhydride) 

\ -> CH3CKC3CH2— CHa— NH--CO . CH3 (I.) 

CH30<CI>CH2— CHa— NH— SO2— CeHg (11.) 
In the case of the acetyl derivative (I.), the substance (III.) — 

CH30<;;3CH2— CHjj— N(CH8)— CO . CH3 (III.) 
is formed by the v HI 

action of sodium and H0<r3CH2— CHg— N— CO . CH3 (IV.) 
methyl iodide, and — 

this on treatment Hydrolyzed 
with HI gives (IV.), with cone 
which then loses its H0<( X^Ha— CHg— N— H (V.) 

acetyl group when I 

hydrolyzed with CHg 

concentrated HCl in sealed tubes. The benzene-sulphonyl de- 
rivative is treated in a similar manner, and the corresponding 
ethyl-amine is obtained by using ethyl iodide instead of methyl 
iodide. 

The Physiological Action of these Compounds. — The re- 
lation between the chemical structure and the physiological 
(sympathomimetic) action of amines has formed the subject of 
an extended investigation by Barger and Dale.^ Dakin' and 
Loewi and Meyer ^ had examined many of the ketones of the 
general formula (H0)2CgH3— CO— CHjj— NE^Ba, and the cor- 
responding secondary alcohols of the type — 

(HO)2CeH3— CH(OH)— CH2— NE1R2 



1 Walpole, J. C. S., 97 (1910), 941. 

s Barger and Dale, Joum, of Physiol, 41 (1910), 19-59. 

sDakin, Proc. Boy. Soc., 76 B (1905), 498. 

* Loewi and Meyer, A. 0. P. P., 53 (1905), 213. 



ADRENALINE AND DERIVATIVES OF ETHYLAMINE 147 

and they found that in most cases, as for example with adrena- 
line itself, reduction to the secondary alcohol greatly increased 
the adrenaline-like action, hut where B^ and B^ represent 
relatively complex radicles, Dakin found no such increase of 
activity on reduction. The physiological effects examined hy 
Barger and Dale were not confined to rise of blood pressure, 
but included dilatation of the pupil, action on the cat's uterus, 
etc., for the details of which the original paper should be con- 
sulted. Besides the various compounds that have been de- 
scribed in the preceding sections of this chapter, various other 
amines were examined. 

Of the various aliphatic amines that were investigated, the 
only ones which were found to produce a marked rise of blood 
pressure were the higher open-chain primary amines, such 
as amylamine, CgH^^ . NHg, and hexylamine, G^H^j . NHg. Of 
these, the normal compounds with unbranched side chains were 
found to be more active than the corresponding iso compotmds 
with branched side chains. Trimethylamine, N(Gn3)3, has 
practically no pressor action, and neither has tetraethylam- 
monium iodide, N(C2H5)4l. Cadaverine, NHj . [CHJg . NHg, 
the only diamine examined, was found to have the opposite 
action (depressor instead of pressor). 

A large number of fatty-aromatic amines without a phenolic 
hydroxyl group were also investigated, and it was found that 
marked sympathomimetic action was associated only with those 
containing an amino group attached to the second carbon atom of 
the side chain. )8-phenyl-ethylamine, CgHg — CHg — CH^ — NHg, 
for example, produces all the characteristic sympathomimetic 
effects. In the series containing two phenolic hydroxyl groups 
in the 3-4 position, the introduction of an aliphatic hydroxyl 
in the ^S-position of the side chain, and the methylation of the 
amino group have an important effect in intensifying the action, 
but in the present series, this does not hold, methyl-phenyl- 
ethylamine, OgHg — CHg — CHj — NH . OH3, phenylethanolamine, 
C5H5 — ^CH(OH) — CHg — NHg, and methyl-phenylethanolamine, 
CeHg— CH(OH)— CH2— NH . CHg, differing but little in their 
action from phenylethylamine itself. ilc.-tetrahydro-)9-naph- 
thylamine — 

10 * 



r48 SYNTHETIC DRUGS 

CH, 
CH— NH 



i 



2 



\/\/ 



which may be regarded as a derivative of this type, is more 
active than phenylethylamine in producing a rise of blood- 
pressare, but is less active than p.-hydroxyphenylethylamine 
(tyramiine), the simplest member of the next series, namely : — 
Amines with one Phenolic llydrox}^ Group. — The sources 



and preparation of many of these have already been men- 
tioned. Methylation of the amino group produces very little 
increase in the activity, HO— CeH^-^-CHa— CH2— NH . CH3 
(see page 145), being only very slightly more active than the 
primary amine, while the ethyl derivative — 

HO— CgH^— CH2— Cfig— NH-^gHg 

is less active than either the methyl derivative or .the parent sub- 
stance. The tertiary ba8e,,H0— CgH^— CH^— CH2— N(CH3)2, 
which is the alkaloid hordenine, has a relatively very 
weak action, but the quaternary base, hordenine methiodide, 
HO— CgH^— CHj— CH2— N(CHj|)3l, although it has no sym- 
pathomimetic action, is of interest as it is one of the few 
exceptions to the rule of Crum Brown and Eraser that quater- 
nary bases have a curare-like action. Instead, its action re- 
sembles that of nicotine, which is a physiological antagonist of 
curare. 

Destruction of the basic property is accompanied by loss of 
activity, acetyl p.-hydroxyphenylethylamine — , 

. , , HO— CgH^- CH2— CHjj— NH . CO . CHj, 

for example, being inactive. Tyrosine ethyl ester — 

.COOC2H5 
HO— CeH^— GH2— CH< 

^NHa 

is also inactive. A phenolic hydroxyl group in the 3 position is 
about as active as in the 4 position, the meta-hydroxy compound, 

^ ^ Ha — CHg — NHg, closely resembling the corresponding 
HO"^ 



ADRENALINE AND DERIVATIVES QF ETHYLAMINE J49 

para-derivative (tyramine), but in the 2 position it has no effect, 

OH 

ortho - hydroxyphenylethylamine, ^ ^ — CH2 — CHj — NHj, 
being no more active than phenylethylamine itself. 

Amines with two Plienolic Hydroxy! Compounds. — The 

following compounds in which the two hydroxyl groups are in 
the 3-4 position were tested : — 

(a) Derivatives of aceto-catechol (Icetones), 

(1) Amino-aceto-catechol, (HO)2C6H3— CO— CH2— NHg. 

(2) Methylamino-aceto-catechol — 

(HO)2CeH3— GO— CHa— NH— CH3. 

(3) Ethylamino-aceto-catechc^ — - . - • , 

(HO)2C6H3— CO— CH2— NH— C2H5. 

(4) Propylamino-aoeto-oatechol — 

(HO)2CeH3— CO . CH2— NH— C5H7. 
(6) Trimethylamino-aceto^catechol chloride — 
(HO)2C,H3— C0-CH2-N(CH3)3C1. 

(b) Derivatives of ethyl-catechoL 

(6) Amino-ethyl-catechol, (HO)2C6H3— CHj— CHg— NHg. 

(7) Methylamino-ethyl-catechol — 

(HO)2C6H3— CH2— CH2— NH— CH3. 
(8)-Bthylamino-ethyl-catechol — 

(HO)2CgH3 — CHg — CHg — NH — C2H5. 

(9) Propylamino-ethyl-catechol — 

(HO)2C6H3— CH2— CH2— NH— C3H7. 

(10) Trimethylamino-ethyl-catechol chloride — 

(HO)2CeH3-CH2-CH2— N(CH3)3C1. 

(c) Derivatives of ethanoUcatechol {secondary alcohols). 

(11) Amino-ethahol-catechol — 

(HO)2CeH3CH(OH)— CH2— NHg. 

(12) Methylamino-ethanol-catechol (adrenaline) — 

(HO)2CeH8— CH(OH)— CH2— NH— CH3. 

And also-7- 

(13) 2-4 dihydroxy-co-amino-acetophenone ^ — 

1 TuUn, J. C. S., 97 (1910), 2496-2624. 



I5» 



SYNTHETIC DRUGS 



OH 

H0<13— CO— CH,— NHj. 

II was found that catechol itself has no sympathomimetic 
action, although it produces a rise of blood-pressure. The 
following table shows the comparative strength of the action of 
the various amines in causing a rise of blood -pressure : — 



Sabsbmce (nnmbered u bofMe). 
(I) (I 

<3{\ 



(13) r- (r-adrenaliDB) 

The ratios shown are only approximate, and vary to some 
extent with the sensitiveness of the animal. The compound 
numbered (7), which was obtained from an isoquinoline de- 
rivative, causes a more prolonged rise of blood -pressure than 
adrenaline. The quaternary bases numbered (5) and (10) re- 
semble hordenine-methiodide in having a nicotine-like action. 
This is less than that of hordenine-methiodide in the case of (5), 
and greater in the case of (10). Although these baaes produce 
a rise of blood-prea§ure, they are not included in the above 
table, as their action is not truly sympathomimetic, as is 
evidenced by their action on other organs. The substance 
numbered (13) on the list, having the hydroxyl groups in the 
2-4 position, is no more active than the corresponding com- 
pound H0<[ ^^>— CO — OHj— NHj, having one hydroxyl in the 
i position. 

Further evidence of the non -significance of a hydroxyl 
group in the 2 position is shown by the trihydroxy compounds, 

HO OH 
amino-adeto-pyrogallol, H0< ( ^ — CO , CHj — NHj, and amino- 

HO OH 
etbyl-pyrogallol, H0< >— CH,— CH^— NH„ which, although 
more susceptible to ,oxidation than the 3-4-dihydroxy com- 



ADRENALINE AND DERIVATIVES OF ETHYLAMINE 151 

pounds, show no increased sympathomimetic action in com- 
parison with the latter. 

The main conclusions are summed up by these investigators 
as follows : — 

" (1) An action simulating that of the true sympathetic 
nervous system is not peculiar to adrenine, but is possessed 
by a large series of amines, the simplest being primary fatty 
amines. We describe all such amines and their action as 
' sympathomimetic* 

" (2) Approximation to adrenine in structure is, on the 
whole, attended with increasing intensity of sympathomimetic 
activity, and with increasing specificity of the action. 

'' (3) All the substances producing this action in character- 
istic manner are primary and secondary amines. The qua- 
ternary amines corresponding to the aromatic members of the 
series have an action closely similar to that of nicotine. 

'* (4) The optimum carbon skeleton for sympathomimetic 
activity consists of a benzene ring with a side chain of two 
carbon atoms, the terminal one bearing the amino group. 
Another optimum condition is the presence of two phenolic 
hydroxyls in the 3-4: position relative to the side chain ; when 
these are present, an alcoholic hydroxyl still further intensifies 
the activity. A phenolic hydroxyl in the 2 position does not 
increase the activity. 

** (5) Catechol has no sympathomimetic action. 

" (6) Motor and inhibitor sympathomimetic activity vary to 
some extent independently. Of the catechol bases those with 
a methylamino group, including adrenine, reproduce inhibitor 
sympathetic effects more powerfully than motor effects: the 
opposite is true of the primary amines of the same series. 

"(7) Instability and activity show no parallelism in the 
series." 



CHAPTER X. 

DEEIVATIVES OF PHENOL (ANTISEPTICS). 

The entrance of a hydroxyl group into the benzene nucleus 
increases its solubility and its reactivity, and, as might be 
expected, these changes are accompanied, by^jLiuincrease in 
its physiological activity and its antiseptic powers. Ighenol, 
GgHgOH, was the first antiseptic to be widely used, and its 
antiseptic powers are increased by the, entrance of halGgeEfftr 
addrtionaTKyd roxyl gro ups into the nucleus. Tl^e entrance of 
more hydroxyl groups adjacent to the "Erst, also increases the 

toxicity of the substance, phenol, [ ] , being less toxic than 

/\0H 
catechol, __,, and this in its turn being less toxic than 
kJOH ^ 

/NOH 
pyrogallol, I U^' 

. OH 

On the o ther hand, the entrance of alkyl groups into'^the 
nucleus lowers the toxicity and increases the antiseptic pro- 
perties,"^ and for this reason the three isomeric cresols, 
CgH4(0H)(CHg), are better^antiseptics th an ph enpj. Unfortu- 
nately this advantage is marred by the fact that the y a,re m uch 
less so luble in water t han phenol, and hence many atte mpts 
have Feen made to obtain derivatives of cres ol which shou ld 
retain their antiseptic properties, and yet be- more soluble in 
water. 

The cresols form an emulsion with (hard) yellow soap, and 
an emulsion of this sort is known as Creolin , but it suffers 
from the drawback that it is demulsified by mineraP acids, 
alkalies, or common salt. A solution of the cresols in soft 
soap is known as Lysol, and has attained wide use as an anti- 
septic. It is prepared by mixing the crude coal-tar cresol 

152 






DERIVATIVES OF PHENOL (ANTISEPTICS) 153 

(cresylic aoid) with linseed oil in presence of alcohol until 
completely saponified, and the final product dissolves easily in 
water.i 

L ysol solutions suffer from the drawback that they vary in 
their a ntisept ic power according to the amount of cresol present, 
and lEenoe they have to be tested bacteriologically, but they 
possess the advantage of being less poisonous than phenol or 
mercuric chloride. 

The oreso ls ca n also be rendered soluble in water by mixing 

th em with the sodium salts of organic sulp honic acids. Thus 

the cresols and other insoluble substances can be brought into 

solution by mixing them with the neutralized products obtained 

from the action of sulphuric acid on resinous oils, etc. 

.OH 
The sodium salts of cresotinic acid, CH, . C6Ho<; , 

^COOH 

salicylic acid, and of various fatty acids, can also be used to 
render the cresols soluble. The only substances of this type 
which are of practical importance are solutions of cresol in soap, 
but a solution of cresol in sodium cresotinate has been sometimes 
used internally under the name of Solveolf as a substitute for 

OH CH, 
guaiacol and creosote. Thymol, GK^ \ y >CHy , is used as 

^CH3 
an antiseptic and anthelminthic,^ but for the latter purpose 
thymol carbonate has been recommended instead. It is pre- 
pared from thymol by the action of carbonyl chloride, COClg, 
and is called ThymatoL 
The polyhydric phenols have not been much used in thera- 

HO/NOH 
peutics. Besorcinol, I , has, however, found consider- 

able application in dermatology, and its acetyl derivative, 
CgH4(0H)(0 . CO . CHg), is used in the same way under the 

OH 
name of Euresol. Pyrogallol, ^^)>0H, is also used in some 

skin diseases on account of its reducing properties. The high 

1 D. B. P., 52,129. 

' Anthelminthic is a tenn denoting a substance used as a poison for in- 
testinal parasites, such as tape- worms, thread-worms, etc. 




154 SYNTHETIC DRUGS 

HO 

price of phloroglucinol, ^ ^ H, has prevented it from coming 

HCT"^ 

into therapeutic use. 

A mixture of various phenyl-sulphuric acids, known as 
Aseptolf is obtained by allowing cold fuming sulphuric acid to 
act on phenol y and adding alcohol to the reaction product. The 
substance thus obtained is unstable and liberates phenol, but 
has no special value. 

The naphthols are not much used in therapeutics ; a-naphthol 

HO 

a-naphthol. /3-naphthol. 

is more poisonous than ^-naphthol, and so only the latter finds 
any therapeutic application. Its sodium salt is soluble in water, 
and has received the name Microcidin, A better-known deriva- 
tive is Epicarin — 

HO . CioHg . CHg ^ y 

OH COOH 

a non-corrosive antiseptic which is strongly acid and forms 
soluble salts. It is said to be useful in skin diseases, such as 
scabies. 

An extended investigation on the effect of substituting halogen 
atoms or alkyl groups for hydrogen in the nucleus of phenol, 
and on the germicidal power of other phenolic derivatives, has 
been carried out by Bechhold and Ehrlich.^ The antisept ic 
power of these compounds was compared by finding the amount 
o f the phenol required to prevent the grow th of certain bacteria 
under standard conditions, the diphtheria bacillus being the one 
usually chosen. It was found that the en trance of chlorine o r 
bro mine into the nucleus of phenol is accompanied by an in- 
crease in the antiseptic power. Trichlor-phenol was found to 
be t wenty-fivfT tiT^ftH an d tri-bromjhenol fort y-six tim es as 
active as phen ol itsel f. TetracElor-, pentachlor-, and" penta- 
brom-phOTols^were increasingly active in the order given, the 

1 ZeU. physiol Cham,, 47 (1906), 173. 



DERIVATIVES OF PHENOL {ANTISEPTICS) 155 

last-named being five-hundred times as powerful in its aotion 
as phenol itself. In the early part of this chapter it was stated 
that the entrance of alkyl groups into the nucleus of phenol 
(as in the cresols) increases the ai^iseptic power, and this was 
found to be the case with the halogen derivatives of the phenols 
also. The tetrabrom derivatives of all three cresols were found 
to be far more active in their germicidal properties than tetra- 
chlor- or tetrabrom-phenol, the derivative of ortho-cresol being 
slightly more powerful than the meta or para isomerides. A 
one-per-cent. solution of this substance takes less than two 
minutes to kill the diphtheria bacillus, whereas a corresponding 
solution of phenol requires more than ten. As the toxicity of 
this compound is stated to be comparatively slight, it might 
find useful application, but the toxicity is apparently still too 
great to permit of its being used internally. 

In f act, although it was found that the entrance of a bromine 
atom reduces the toxicity and characteristip^on^prilsiyejiction 
of pheho Htself , nevertheJess t he co nclusion was arrived^at Jhat 
none of these compounds were^suitable^fotr flJieJii^ dis- 

infectants, as they were^o more damaging to bacteria than to 
the animal body. The fur ther introduction of halogen is accom- 
panied bya rise of toxicity, that of the tribrom- and trichlor- 
phenols being aboui equalTo that of phenol itself, while the 
tetra- and penta-halogen derivatives are extremely toxic. 

The simple phenolic compounds and their halogen derivatives 
are therefore not suitable for internal disinfection, but greater 
success has attended the use of phenolic derivatives containing 
a second group in the molecule, which lowers the toxicity of 
the compound. 

The introduction of a carboxvl group, as is usually the case, 
lowers the to xicity. It is true that it greatly lowers the anti- 
septic power ^f phenol, but in sj>itaiot^this^ilie>iifli6rcarty6^^ 

acid of phenol, I (salicylic acid), has marked antiseptic 

properties, and it has proved to be of great value medicinally. 

Another type of phenolic derivatives which has proved 
of value as an internal antiseptic, is represented by guaiacol, 



AOCH3 



Uo] 



^Salicylic acid and its derivatives are used more on 



156 SYNTHETIC DRUGS 

aooonnt of their Talue in lowering the temperature and dimin- 
ishing the pain in rheumatism rather than for the sake of their 
antiseptic properties, bat the aoid and its ester with phenol 
(salol) are also used as antiseptics. The derivatives of salicylic 
aoid will be discussed in the next section, and those of guaiacol 
in. the one after that. 

Salicylic Acid and Salols. — As has been so frequently 
pointed out, the introduction of a carboxyl group into phenol 
lowers its physiological activity. Meta-hydroxy- and para- 
hydroxy-benzoic acids are practically inert physiologically, but 
salicylic acid^ in addition to having a very slight toxicity, pos- 
sesses special therapeutic properties which are of very great 
value. 



Vh 




COOH 

UoH 

m.-hydioxy -benzoic acid. p. -hydroxy-benzoic acid. Salicylic acid. 

The most important of these is a powerful action against 
most of the symptoms of acute rheumatism, which is marvel- 
lous in its intensity. Salicylic acid also possesses marked 
antiseptic properties, for which it is often used to cheiak gastric 
fermentation, as its irritant action on the stomach is much less 
than that of phenol, and for the same reason it is often used 
to prevent putrefaction in milk, beer, etc. In the body it is 
rapidly absorbed, and circulates as the sodium salt, which is 
often used therapeutically instead of the free acid, as of course 
its action is the same, and it has the advantage of being far 
more soluble in water. 

Salicylic acid was first synthesized by Kolbe ^ by the action 
of carbon di gxid e on phenol. Originally this was carried out 
by passing carbon dioxide into hot phenol in the presence of 
sodium, but it was found better for technical purposes to 
prepare dry sodium phenate, C^HgONa, and to pass carbon 
dioxide into this. Even by this method, howefVer, only a 50- 
per-cent. yield of salicylic acid was obtained, and if potash 
were used instead of soda, para-hydroxybenzoic acid was the 

1 AntuUm, 113 (I860), 115 ; 125 (1866)r 201 ; D. K. P., 426. 



DERIVATIVES OP PHENOL (ANTISEPTICS) 157 

chief product. This process was greatly improved by Schmitt,^ 
who heated sodium phenyl carbonate — 

IJh ^ lJ_CO-^Na 

under pressure at 140'' C, by which means a quantitative yield 
of sodium salicylate was obtained. This process is also applic- 
able to the preparation of naphthol-carboxylic acid and oxy- 
quinoline-carboxylic acid.^ 

Salicylic acid and its sodium salt frequently produce un- 
pleasant gastric symptoms, and to overcome this defect various 
derivatives have been prepared, one of which, acetyl-salicylic 

., A— O— CO.CHo . , . ^. 

acid, I I , IS of very great miportance. This 

substance is known under various trade names, such as Aspirin, 
etc. 

It has the characteristic action of salicylic acid, being hydro- 
lyzed in the intestine with liberation of sodium salicylate, and 
it also has a slight sedative action of its own. It is a favourite 
remedy for feverish colds, headaches, etc. 

It was first obtained by heating salicylic acid with excess of 
acetic anhydride or acetyl chloride, but a better yield is obtained 
by carrying out the acetylation in the presence of a condensing 
agent, such as sulphuric acid, zinc chloride, or sodium acetate. 
Propionyl, butyryl, and other acyl derivatives of salicylic acid 
have been obtained in the same way. 

Of these, methylenecitrylsalicylic acid is known as Novaspirin, 
salioylosalicylic acid as Diplosal, and succinylsalicylic acid as 
Diaspirin, The calcium salt of acetylsalicylic acid is known 
as Soluble Aspirin or Kalmopyrin, and the sodium salt as 
Tylnatrin. These, and also the lithium salt, Hydropyrin, are 
more soluble in water than is Aspirin itself, which they resemble 
in their therapeutic effect, whilst) the last named has also the 
characteristic action of lithium salts (0/. p. 220). 

A substance which is isomeric with aspirin has been obtained 
by the action 1>f acetyl chloride on salicylic acid in presence 
of ferric chloride. It is an aeeto-salicylic acid of the formula 
(CH, . CO) . CeHj . (OH)(COOH), and is not toxic, but it has 

1 D. R. P., 29,939. «IWd., 31.240. 



158 SYNTHETIC DRUGS 

far less antiseptic power than salicylic acid itself. Salicyl- 

.COOH 
acetic acid, CJ3,/( , in which the hydroxylic 

\0— CH2— COOH 

hydrogen is replaced by an acetic acid residue, ( — CHj — COOH)^ 

instead of by the acetyl group, (CO . CH,), was first obtained 

by the oxidation of the ortho-aldehyde of hydroxyphenyl -acetic 

acid.^ Subsequently, improved methods of preparing it were 

devised,^ but this substance does not appear to have come into 

use as a drug. 

Schmitt's modification of Kolbe's salicylic acid synthesis 

has been extended to several other substances. For example, 

OCOOH 
OH has been prepared from guaiacol, but it has not 
— 0— CHg 
found its way into therapeutics, and from a- and )3-naphthols 
the corresponding carboxylic acids have been obtained, in each 
of which the carboxyl group is in the ortho position to the 
hydroxyl group. The acid (I.) thus obtained from ;3-naphthol is 
very unstable!, splitting up into naphthol and carbon dioxide, but 
if the temperature at which the synthesis is carried out be raised 
to 200^-250'' C, a stable acid (II.) is obtained. 

COOH 
/VNOH /VNOH 



"Ar 




OOH 



Of the various derivatives of salicylic acid that have been 

.0 . CO . CHj 

mentioned, acetyl-salicylic acid, GJB.^^ , is the only 

^COOH 

one of real practical value, but other substances have been used 
instead of salicylic acid itself, chiefly on account of the distrust 
with which synthetic salicylic acid was at one time viewed. 
This distrust arose from the fact that the synthetic acid used 
often to contain the therapeutically useless para-hydroxybenzoic 
acid, as well as sometimes being contaminated with the posi- 
tively harmful cresols. To make sure of obtaining a natural 
product, some physicians preferred to prescribe the glucoside 

1 Ber., 17 (1884), 2996. « D. R. P., 93,110, 110,370. 



DERIVATIVES OF PHENOL (ANTISEPTICS) 159 

salicin instead of salicylic acid itself. This glucoside is hydro- 
lyzed by the organism, with liberation of saligenin (salicyl 

.CH2 . OH 
alcohol), GJ3.^\ , which then forms salicylic acid by 

\0H 

slow oxidation. In this way, the use of saligenin or salicin 
ensures a gradual action of the salicylic acid. Saligenin may 
be synthesized by the action of formaldehyde on phenol — 

Ortho-cotmaric acid, M^g^^^""^^^^, bears the same 

relationship to cinnamic acid, CgH^ — CH=CH . COOH, as sali- 
cylic acid does to benzoic acid, and as cinnamic acid is more 
physiologically active than benzoic acid, it was to be expected 
that o-coumaric acid would have even more powerful antiseptic 
properties than salicylic acid. This was found to be the case, 
all three coumaric acids having a marked germicidal action, 
which is strongest in the case of the ortho acid. 

Incidentally, it should be noted that sodium cinna/mate has 
been found to be active in promoting leucocytosis, and has been 
recommended in cases of tuberculosis. Its esters with guaiacol, 
phenol, ortho and para-cresol are too irritant to be of use, but 
its meta-cresol ester is free from these drawbacks, and is used 
under the name of Hetocresol as a dusting powder for tubercu- 
lous wounds. A similar compound of cinnamic acid with 
thymol has also been prepared.^ 

A dilute aqueous solution of sodium cinnamate has been used 
in Germany under the name Hetol, and a glycerol solution of 
this substance which has certain advantages over the aqueous 
one was advocated by Morgan in 1902. The use of drugs, 
such as sodium cinnamate and sodium ortho-coumarate, which 
produce leucocytosis,^ appears to have given promising results 
in the treatment of inoperable cancer when combined with 

1 D. R. P., 99.667, 107,280. 

^ Leucooytoflis denotes an increase in the count of the white blood- 
corpuscles. 



/ 



i6o 



SYNTHETIC DRUGS 



local treatment with substances such as copper oleate and 
antimony oxide.^ 

The acetyl derivative of o-coumaric acid which is suitable 
for being taken by the mouth has been introduced by Martindale 
under the name of Tylmarin. 

Salol and Esters of a Similar Type. — The first ester, both 
the components of which are physiologically active, to be used 

in medicine was 9(M, Lloo O (c H (P^^^J^ salicylate). 

The introduction of this substance by Nencki marked an 
important development in pharmacology, and many other 
attempts have been made to convert substances which are 
too toxic for ordinary use into esters from which the active 
component is liberated so slowly that it produces no injurious' 
by-effects. In the case of salol itself the ester on hydrolysis 
in the intestine liberates phenol and salicylic acid, the 
hydrolysis taking place so gradually that the former com- 
ponent can exert its antiseptic effect without, under ordinary 
conditions, giving rise to its characteristic toxic symptoms. 
In this case both components of the ester are active, but this 
'' salol principle," as it is called, can be extended to esters in 
which only the acid or the alcohol is active, but the use of 
which in the free state is hindered owing to the possession of 
toxic or corrosive properties. 

Derivatives of this kind may be classed as " partial salols," 
and comprise two types : — 

(1) Esters in which an active (arom'atic) acid is esterified 
with an inert hydroxylic substance (alcohol), and which there- 
fore bear a general resemblance in their physiological action to 
the acid from which they are derived, but which may differ 
from it in being free from harmful by-effects. 

(2) Esters in which an active hydroxyl compound (alcohol 
or phenol) is esterified by an inactive acid. In this case the 
action of the substance resembles that of the alcohol or phenol, 
the sodium salt of the acid being inert. 

It must not be lost sight of, however, that disinter itself 
may exert a specific action in the unhydrolyzed state {e.g. 

1 H. Lovell Drage, Lancet, 7th November, 1908, p. 1867. 



DERIVATIVES OF PHENOL {ANTISEPTICS) i6i 

triacetin : see Chap. II., p. 22), and therefore in every case the 
physiological action of the ester must he experimentally demon- 
strated before it can be used in therapeutics, as a priori reason- 
ing based on the behaviour of the component acid and alcohol 
might be upset by the specific action of the ester. 

Dealing first with the true salols themselves, it may be said 
with confidence that no other ester of this class is nearly as 
important as salol itself. It was found by Nencki that fatty or 
aromatic acids when allowed to react with phenols in presence 
of zinc chloride, aluminium chloride, etc., yielded ketones, but 
if POCI3 were employed as the condensing agent, esters were 

.OH 
formed. Thus salol itself, GqB.^^^ , is produced ,by 

\C0 . O . CeHg 

heating two molecules of phenol, two molecules of salicylic 
acid and one of POCI3 at 120° C.^ This method has also been 
applied to the preparation of the esters of salicylic acid with 
many other phenols, naphthols, resorcin, etc., and also to the 
preparation of the esters of other acids, such as nitro-salicylic 
and oxynaphthoic. A cheaper and simpler modification of this 
method of preparation is to allow carbonyl chloride to react 
with an equi-molecular mixture of the sodium salts of the 
phenol and of the acid. The ester thus formed can usually be 
separated from the reaction mixture by distilling it o£f with 
steam. In this way an enormous number of esters of a similar 
type to salol have been prepared.^ 

Salol is also obtained by heating salicylic acid alone at 160°- 
240° C, provided that the water split off by the reaction be re- 
moved by distillation, and that the access of air be prevented.^ 

/OH /OH ^ 

.OH .OH 

CeH / = C,H / + CO, 

^COOH \H 

*•*• ■* /OH /OH 

w . OH . CA<^^^- <^K^^; ^'° 

1 D. R. P., 38,973, 39,184, 43,173. 

^Ibid., 46,766, 57,941, 68,111, 70,487; and also Nencki, 0. R., 108 
(1889), 264. « D. R. P., 62,276, 

II 



x6a SYNTHETIC DRUGS 

Another method for the preparation of salol is by heating 
polysalioylide {GjRfi^)x (obtained by heating salicylic acid with 
POClj, see Chap. IV.) alone with phenol.^ 

The higher members of the salol series may be prepared by 
heating salol itself with the higher phenol, whereby the lower 
phenol is replaced by the higher. This method is especially 
suitable for use with phenols which are too reactive to be 
treated with the vigorous condensing agents used in the first 
methods ; e,g, hydroquinone, eugenol, carvacrol, etc.^ 

•• Partial Salols " of the First Type.— Methyl salicylate {oil 
of wintergreen) is the best known of these. The synthetic pro- 
duct is superior to the natural in being free from the irritant 
Jbffects of the latter. It is slower in its action than salicylic acid 
X itself . Ethyl salicylate appears to have a specific action of its 
own, and produces undesirable effects, and hence is not used in 
therapeutics. Mesotan or Ericin is the methoxy-methyl ester of 

.OH 
salicylic acid, CgH.^f . Many esters of 

\C0— O— CH2— OCH, 

glycerol with salicylic acid, benzoic, acid, p.-cresotinic acid, 

and anisic acid have been prepared, such as — 

CH2— O— CO— CeH^—OH CHg— 0— CO— C^H^— OH 

CH— 0— CO— CfiH^— OH CH— O— CO— CfiHg 

CH2— 0— CO— CgH^— OH CH2— O— CO— CeH,— OH 

Trisalicylin. Disalicylbenzoin. 



CHg— O— CO— CgH^— OH 
and CH— OH 
-OH 



/ 



CHo— 



2 

Monosalioylin. 
The last named is used under the name of Glycosal? 



1 D. R. P., 73,452. » ZW., 111,666, 

» J&id., 58,396, 126,311, 127,139, 



DERIVATIVES OF PHENOL (ANTISEPTICS) 163 

The monoglycol ester of salicylic acid, 

CH2--O— CO— OgH^— OH 



CHg— OH 

is known as Spirosal, 

Salacetol is obtained by the action of monochloracetone on 
sodium salicylate — 

/OH 

. ^COONa + CI . CH^ . CO . CH^ 

/OH 
- CeH / 

^CO . O— CHg . CO . CH3 + NaCl 

and is therefore the salicylic ester of acetol, HO — CH^— CO — 
CH3. It is rapidly saponified in the intestine, but has no 
particular advantage over salicylic acid.^ 

The methyl esters of the acyl salicylic acids have also been 
used medicinally. Methyl acetylsalicylate is known as Methyl^ 
rhodiny-9,nd methyl benzoylsalieylate b,s^ BenzosaUn. 

*' Partial Salols" of the Second Type, in which only ihs 
phenol is the active part, comprise carbonates and esters oi 
fatty acids. Of these, the esters of guaiaool and creosote are 
of special importance, and will be considered in the next section 
of this chapter (which deals with creosote and guaiaool deriva- 
tives), together with the general methods of their preparation. 
Thymol carbonate is known as Thymatol. 

True Salols. — Of esters of the type of salol in which both 
components are active, salol itself is the most important, and next^ 

to it comes )8-naphthol salicylate, fY\—^—^^—<rZy* ^^^^ 

is known as Betolj and as Naphtholsalol. The benzoate of )3- 
naphthol is also used to a considerable extent under the name of 
BenzonaphthoL Menthyl salicylate is used medicinally under 
the names of Salimenihol and SalU.. In addition to the esters 
of salicylic acid itself, the phenyl esters of acetylsalicylic and 
of salicylosalicylic acid are used, and are known respectively as 
Vesipyrin and Disalol. 

1 D. B. P., 70,054. 

II* 



L^ 



i64 SYNTHETIC DRUGS 

In general it is only the monobasio aoids which lend them- 
selves in an economical manner for use as salols, as the esters 
of polybasic acids usually only split off one molecule of the 
phenol, the rest being excreted still in combination with the 
acid. Thus, for example, triphenyl phosphate, (CgH50)3PO, is 
hydrolyzed in the intestine into diphenyl-phosphoric acid, 

(CgHgO)-?^ , and phenol, C^HgOH, the former not being 

further decomposed in the organism, and thus only a third of 
the phenol is utilized. 

Another type of salicylic acid derivative comprises those 
in which it is combined with basic radicles. Salicyl-amide, 
OH 

^~y — CO — ^NHj, is more soluble than salicylic acid, and has 
a more marked analgesic action. Many compounds have been 
prepared in which salicylic acid is combined with substances 
having antipyretic and analgesic properties, especially the de- 
rivatives of acetyl-para-amino-phenol. The salicylate of acetyl- 



para-amino-phenol, HO ^ ^ NH . CO . CHg, is known as 
Salophen} In the same manner lactylamino-phenol can be 
condensed with salicylic acid.^ 

Quaiacol, Creosote, and their Derivatives. — ^Beechwood 
tar has long been used in the treatment of phthisis, and the chief 
active ingredients appear to be guaiacol and creosol. 

CHj CH3 

OOCH, AOCH, AOH 

OH UoH ""^ U0CH3 

Guaiaool. Creosol. 

These can be obtained from the beechwood tar, but guaiacol is 
also largely produced by synthetic methods. It can be obtained 

^OH 

is too expensive for technical use, and a cheaper synthesis is 
that which starts from ortho-anisidine. This substance is pre- 



by the partial methylatipn of catechol, 1 ^, but this method 



1 D. K. P., 62,633, 69,789. « Ihid., 82.635. See also Chap. V. 



DERIVATIVES OP PHENOL (ANTISEPTICS) 



i6s 



pared from ortho-nitro-phenol by methylation and subsequent 
reduction. It is then diazotized, and the solution poured into 
sulphuric acid containing a large quantity of sodium sulphate, 
heated to 135°-160° C, whereupon the guaiacol distils oVer 
with the steam as it is formed. In this way the production of 
by-products is diminished. 



/\0H 

Jno^ 



AOCH3 

Uno^ 



AOCH3 

UnH2 



AOCH3 
Jn^oh 



/NOCH. 



Creosol has been obtained in a similar way from 




, but 



the preparation of this compound from ortho-cresol is appar- 
ently too expensive for it to be used commercially. 

Guaiacol, like phenol, is corrosive and poisonous, and it is 
probable that creosol would be less toxic, though more strongly 
antiseptic, in the same way as cresol and phenol. 

/NOCoH. 
Guaiatholj I , and other higher homologues have 

\/0H 

been prepared by heating catechol and the required alcohol 

under pressure with zinc chloride at 160°-220° C, but they are 

more expensive than guaiacol and have no advantage over it. 

With the object of diminishing the unpleasant and toxic 
properties of guaiacol and creosote, various derivatives have 
been prepared in which the hydroxyl group is esterified with 
an acid according to Nencki's salol principle. Carbonic acid 
was the first used, and various other organic and inorganic 
acids have also been tried with varying degrees of success. In 
every case, the action of the compound is due to the guaiacol 
split off in the intestine. 

Guaiacol carbonate, known as Duotal, is prepared by the 
action of phosgene on an alkaline solution of guaiacol.^ 




oca 



0CH3 CH30 



+ COCl, 




\ 




C^ + 2NaCl 



Ductal is thus obtained as an insoluble preparation, which 



1 D. R. P., 68,129. 



166 SYNTHETIC DRUGS 

has less toxicity and unpleasant taste than gnaiaool itself, bat 
which is not quite tasteless. In the same way, carbonates of 
menthol, borneol, carvacrol, thymol, creosol, eugenol, etc., have 
been prepared, and also the corresponding esters of carbamic 
acid nsing chlorocarbonic amide instead of GOGlj — ^ 

XONa + CI . CO . NHj, - NaCl + XO . CO . NHg. 

This process, besides being used for the pure substances, 
may also be applied to the mixture of phenols comprising 
creosote, by which means a mixture of neutral carbonic esters 
free from corrosive properties is obtained, which is called 
creosote carbonate. 

Phenolic substances, such as guaiacol, can also be converted 
into alkyl carbonates instead of carbonates by the action of 
chloroformic ester on the hydroxyl compound or its sodium 
salt — 

XONa + CI . CO . O . C2H5 = X . O . CO . O . CgH^ + NaCl ; 
e.g.— 

CgH4^ from guaiacol, 

^0— CO . . C2H5, 

and 

.COOCH3 
CgH^^ from oil of wintergreen. 

^O— CO . . CgHfi 

The carbonate of catechol, C^H.^; yCO, forms addition 

\o/ 

products with compounds containing an alcoholic hydroxyl 
group or a primary or secondary amino group, whereby one of 
the hydroxyl groups of the catechol is regenerated with the 
formation of a mixed ester of carbonic acid.'^ 
e.g.— 

/\/^\ ^^^0-CO-OC,H, 

I I C0 + C2H,0H = | I 
\/\0/ \/\0H 

^ D. B. P., 11 ,856, 116,366, for variations of this method. 
^Ibid., 92,535. 



DERIVATIVES OF PHENOL {ANTISEPTICS) 167 

and 

/O^ ^O-CO-NH-C^H, 

In the preparation of carbonates of phenols by the phosgene 
method, it may happen that those which are easily decomposed, 
such as the-derivative&of iso-eugenol or menthol, are broken 
up, and therefore the method requires modification. In these 
cases, diphenyl or diethyl carbonate is first prepared, and this 
then made to react with the desired phenol.^ 

For example, with iso-eugenol — 

COCI2 + aCeHfiOH = CO(OCeH5)2 + 2HC1, 

C H 
C0(0CeH,)2 + 2CeH3<^-06H3 

CO + 2aH50H. 

OHTT 



\ /OCH3 

0-CeH3< 



C3H5 

As the phosphites are said to be useful in the treatment 
of tuberculosis, it is not surprising that guaiacol phosphite, 
P( — O — CgH^ — 0CHg)3, has been prepared. It is a crystalline 
powder, which has the advantage over the carbonate and 
phosphate of guaiacol in being soluble in fatty oils, and it is 
prepared by suspending guaiacol and an equivalent of soda in 
alcohol and adding one molecular proportion of PGI3 to the 
cooled mixture. It is then heated to boiling and the alcohol 
distilled off.^ Substances such as this are known under the 
names of Phosphatol, Creosote-phosphite , etc. 

Guaiacol benzoate is known as ** Benzosol" and the acetate 
as " Eucol " ; the cinnamate, which is known under the name 
of " Styracol" is said to be a very good antiseptic and anti- 
tubercular, free from harmful effects. Cacodyliagol is guaiacol 
cacodylate, (CH3)2As .0.0. CeH4(OCH3),H20. 

Another type of guaiacol derivatives is that in which the 

1 D. R. P., 99.057. ' Ibid., 96,678. 



i6d &VNTMBTIC DrV&S 

hydroxylic hydrogen is replaced by alkyl groups Or other 
groups in which the hydroxylic oxygen is directly united to 
carbon. Veratrol may be included in this class, but it does 
not show the physiological action of guaiacol in any great 
degree, and probably does not split off any guaiacol in the 
organism. If, however, instead of replacing the hydrogen by 
a methyl group as in veratrol, one replaces it by a larger 
group, then the resulting compound is less stable, and guaiacol 
is regenerated to a greater or less extent in the organism. 
The glycerol ether of guaiacol — 

CHa— OH 



i 

k 



H— OH 



fG.2 — O — G^EL^ — OGS3 

known as " Chuaiamar" is one of the most important of this 
type. It is soluble in water and is prepared by the action of 
mono-chlorhydrin, CH2(0H)— CH(OH)— CHgCl, on an alka- 
line salt of guaiacol, or by the interaction of guaiacol and 
glycerol in presence of condensing agents. Glycerol ethers of 
other phenols have been prepared in the same manner. Taste- 
less soluble derivatives of guaiacol and other phenolic substances 
are obtained by the action of alloxan on phenols in presence of 
certain condensing agents, such as n2S04, HOI, ZnOlg, etc.^ 

CO— NH CO— NH 

/ \ / \ 

E_0— H+CO CO = B— O— CH CO 

\ / \ / 

CO— NH CO— NH 

An insoluble guaiacol preparation, known as ** Cetiacol " or 
" Palmaicol" is obtained by the action of guaiacol in sodium 
ethylate on spermaceti oil at 80° C.^ It is said to be without 
irritant action on the alimentary canal. 

Ouaiaperol is an addition product of guaiacol and piperidine, 
having the formula C5HiiN,(C7H802)2. The object aimed at is 
to combine the action of guaiacol with the tonic action of piperi- 
dine on the heart and circulation. It is said to be without 
irritant action.^ 

1 D. R. P., 113,722. 2Engl. Pat., 16,349. 

3 Chaplin and Tunnioliffe, B. M, J, (1897), p. 137. 



DERIVATIVES OP PtiEML (ANTISEPTICS) 169 

Creosoform is a product obtained by the condensation of 
formaldehyde and creosote, and has been recommended as an 
internal antiseptic. A substance of this type recently intro- 
duced is ^^ HexamecoU" a preparation of guaiacol and hexa- 
methylene-tetr amine .1 It is a powder which readily splits up 
into its components {e.g. when rubbed on the skin), and is 
recommended as an external disinfectant. 

Another class of guaiacol derivatives comprises substances 

which do not regenerate guaiacol in the organism. It was to 

be expected that the entrance of a sulphonic acid group into 

guaiacol would lower its activity, and such is found to be the 

/OH (1) 
case. By sulphonating guaiacol at 70°-80° C, CgHgf-OCHj (2) 

\sO3H (3) 

is obtained, which is therapeutically useful, its potassium salt 

known as " Thiocoll " being soluble and non-irritant. If the 

sulphonation be carried out at 140°- 150° C, the chief product is 

/OH (1) 
CgHg^OCHg (2), which is of no therapeutic value. The sodium 
\SO3H (4) 

salt of I 

kJL-O— CHg— COOH, known as " Guaiacetin" is 

soluble in water and nearly tasteless, and can be obtained by the 

action of chloracetic acid on catechol in the presence of alkali.^ 

.OH 
Guaiaool-carboxylic acid, CgHg^OCHg, is sparingly soluble, 

\COOH 

and has antiseptic properties, but has no advantage over guaiacol. 

Although not a derivative of guaiacol, " Solveol " is used as 

a cheap substitute for guaiacol to which it has a similar action. 

It is a solution of creosols in sodium para-cresotinate — 



CH 



/V-COONa 
U-OH 



1 Cf. Chap. XI. 

« D. R. P., 87,386 ; see also ibid,, 87,668 and 87,669. 



CHAPTER XI. 

OTHER ORGANIC ANTISEPTICS, EXCLUDING HALOGEN 

COMPOUNDS. 

Organic Dyestuffs and Theories of Ctiemico-Tlierapy. — 

The organic dyesta£fs are of interest both from the practical 
point of view on account of their use in therapeutics, and also 
on account of their importance in the development of the 
theories concerning the mode of action of drugs. 

Many of the diseases caused by microbial or parasitic in- 
fection can be successfully treated by a suitable serum, but 
there are a large number, especially those of protozoal origin, 
which do not lend themselves to serum-therapy. In these 
cases a cure has been sought by chemical means, and at one 
time great hopes were entertained of curing many diseases of 
microbial origin by the use of general antiseptics, such as those 
which have proved so valuable in surgery. Generally speaking, 
however, the results obtained by the introduction of antiseptic 
methods into medicine have been disappointing when compared 
with the success which has attended their use in surgery. 
Various processes such as the intravenous injection of form- 
aldehyde solutions, the inhalation of antiseptic vapours such 
as creosote for consumption, and many others, have not fulfilled 
the hope that was placed in them. This is not surprising 
when it is borne in mind that most antiseptics are quite as 
injurious to the tissues of the higher organism as they are to 
the bacteria (c/. Chap. X.). It has been pointed out^ that a 
greater measure of success may be hoped for in the case of 
those diseases which are caused by protozoa rather than by 
bacteria.. The latter are probably amongst the oldest living 
organisms and have probably acquired a high degree of resist- 
ance, but the former do not appear to have been able to adapt 

» Cushny, Proc. Roy, 8oc, Med., 2, iv. (1909), 49. 

170 




OTtiER ORGANIC AhfTISkPTIC^ i^l 

themselves so successfully to their environment, and the diseases 
they give rise to are very likely of more recent date than those 
caused hy bacteria. 

In some of these diseases favourable results have been obtained 
by the use of a chemical specific, which is not equally fatal to 
all forms of life, but which reacts specifically with certain 
micro-organisms in a manner somewhat analogous to the action 
of the afore-mentioned curative' sera. This is expressed by 
saying that a substance of this type should have a strong 
afl&nity for the parasites (parasitotropic), but should be only 
slightly active to the organism (organotropic). Instances of 
this are afforded by syphilis and malaria, which yield far more 
readily to specific antisepsis, the former to mercury and arsenic 
and the latter to quinine, than do diseases of bacterial origin. 

Our knowledge of the chemical specifics and their probable 
mode of action, we mainly owe to Ehrlich,^ and his success in 
this field was largely due to a careful study of the reactions 
between the parasites and the dyes which reveal them in their 
surroundings. He realized that the relation between a dye 
and a particular type of cell is a chemical fact of great im- 
portance, and that such a dye must contain an anchoring group 
that can enable it to attach itself to the particular type of cell 
in question. To vary the simile, the chemical specific may be 
likened to a poisoned arrow, the point being the particular dye 
which has a selective affinity for the parasite, and therefore 
fixes it. If a poison can be attached to such a dye or to the 
anchoring group of such a dye, the arrow will be not merely a 
dye, but also the desired chemical specific. 

This procedure is not so simple as might be gathered from 
the above, as the attachment of a poisonous element or radicle 
may destroy the anchoring effect of the other groups. On the 
other hand, many dyes are themselves poisonous to certain 
parasites, and act as chemical specifics in these particular in- 
fections. 

For example, some of the triphenylmethane dyes, many of 
the azo dyes derived from benzidine, and various thiazine dyes, 
such as methylene-blue, have a strong parasiticidal action. 

Thus, amongst the dyes derived from benzidine. Trypan Eed 

^ Cf. Chap. I., p. 8. 



172 SYNTHETIC DrVGS 

and Trypan Blue have a strong trypanocidal^ action. The 
former is obtained by tetrazotizing benzidine-orthosnlpbonic 
acid, and coupling with )3-naphthylamine 3-6-diBnlphonic acid, 
ai^d therefore has the formula : — / 

SOjNa 
/ 

n=nCXI>n=n 



/nAn: 



NaSOjisJsJsOjNa NaSOav\/SO,Na, 

the latter is obtained by tetrazotizing o-tolidine, and coupling 
with 8-amino-naphthol (1), 3-6 disulphonic acid ("H" acid), 
and th^iefore is represented by the formula : — 

NHgOH OHNH2 

NaSOglsJ^OaNa CHT CH3 NaSOjlsA/JsOsNa 

I It is noteworthy that all the azo dyes of this series which are 

effective trypanocides have the sulphonic acid groups in the 3-6 

position. Naga Bed which differs from Trypan Bed only in 

the absence of the sulphonic acid group in the benzidine portion 

of the molecule was found to have a strongly poisonous action 

/ on the spirilla of relapsing fever, but it also acts strongly on 

"" the red blood corpuscles. Trypan Bed and Trypan Blue have 

shown good results in the treatment of nagana, especially when 

used in conjunction with certain triphenylmethane dyes such 

as di- and tri-hydroxy malachite greens, and para-rosaniline. 

Malachite Green has the formula : — 



(CH3)2N0-9 =<Z>= N(CH3)2C1, 




and Brilliant Green, which is the sulphate of the corresponding 
ethyl compound, is used fairly extensively as a general anti- 
septic. 

^ The various species of tiypanosomes are the cause of many tropical 
diseases, notably sleeping sickness, which is due to infection by Trypano- 
8oma gamhiense. 



OTHER ORGANIC ANTISEPTICS 



173 



Methylene blue, 



(CHAN 




/^\ 



0^ 



'\S/^\N(CH3),C1, 

is used internally in a variety of conditions suola»9iS rheumatism, 
cystitis, nephritis, etc. This dye was found to have strong 
parasiticidal action on the spirilla of relapsing fever: in test- 
tube experiments, but failed when used on infected animals. 

A dye which is largely used as a paste for external applica- 
tion for stimulatiijg the growth of epithelium over granulating 
wounds,, is §cazl£LMed, an azo dye derived from amidoazo- 
toluene and )8-naphthol, and therefore having the formula, 
CH3 . C^H^ . N : N . CgH3(CH3) . N : N . G^^fi. 

Some of the dyes derived from acridine, 



-\ 




/CH^ 



\ 



N- 



0, 



have recently attracted considerable attention as antiseptics 
both for' external and intravenous use, namely Proflavine^ 3-6 
diaminoacridine sulphate. 



H, 



( 



/ 




NH,. 



N 



and Trypafiavine or Acriflavine, 3-6 diaminomethylacridinium 
chloride, 






h^nUxj^/Jnh^, 



CHg CI. 

The latter was originally introduced by Bhrlich as a trypanocide. 
Proflavine is prepared ^ by the interaction of aniline, form- 
aldehyde and caustic potash, and heating the resulting product 
with aniline hydrochloride, whereby diaminodiphenylmethane 

1 Benda, Ber., 45 (1912), 1787 ; D. R. P., 230,412 ; E. P., 24,662 (1910). 



174 SYNTHETIC DRUGS 

is formed. This is then nitrated, and the product reduced 
with tin and hydrochloric acid, and the .reduction product 
which contains the tin douhle salt of tetra-aminodiphenyl- 
methane, 



h^nU 






2 --2^ J 



is heated in an autoclave at 140° to form 3-6 diaminoacridine. 

To prepare Acriflavine from Proflavine,^ the amino groups 
in the latter are protected by acetylation, and the diacetyl 
compound is then methylated by methyl sulphate or methyl 
toluenesulphonate in nitrobenzene solution. The acetyl groups 
are then hydrolyzed from the resulting compound by heating 
with hydrochloric acid, and on cooling the desired hydrochloride 
crystallises out in red needles. 

Browning and his colleagues have recommended Proflavine 
and Acriflavine in the treatment of wounds, as they have high 
antiseptic power, together with freedom from irritant or 'toxic 
action, and no inhibiting effect upon the phagocytic action of 
the leucocytes or upon the process of healing. Up to the 
present, the clinical evidence appears to be very conflicting, 
but it is probable that good practical results will be obtained 
with these compounds. 

Naphthalene, Pyridine, and Quinoline Derivatives. — The 
antiseptics derived from other cyclic systems, such as naphtha- 
lene, pyridine and quinoline, are none of them so important as 
certain benzene derivatives, such as phenol. The naphthols and 
their derivatives have already been mentioned in connection 
with the phenols, but naphthalene itself has antiseptic pro- 
perties, and on account of its volatility is a useful insecticide, 
and has largely replaced camphor as a means of protecting 
clothes and other fabrics from moths. It is often sold for this 
purpose under the name of " carbon." 

All the pyridine carboxylic acids have strong antiseptic 
properties. Uvitonic acid (2-picolinj-4-6-dicarboxylic acid), 

1 Benda, Ber., 45 (1912), 1795 ; D. R. P., 243,085. 



OTHER, ORGANIC ANTISEPTICS 175 

COOH 

a, is said to be a stronger antiseptic than sali- 
OOH 

N 
oylio acid, but the expense of its preparation has prevented it 
from being used for this purpose. It is produced by the action 
of alcoholic ammonia on pyruvic acid.^ 

Quinoline has an antiseptic action, which is increased by 
the entrance of methyl groups. A quinoline derivative has 
been placed on the market under the name of Ghinosol, and is 
prepared by boiling an alcoholic solution of ortho-hydroxy- 

J 

y 




quinoline, 1^ .J^ J, with acid potassium sulphate .^ The pro- 

^ H( 

duct appears to consist of ortho-hydroxy-quinoline sulphate and 
potassium sulphate. It has been used as an antiseptic both 
internal and external. 

Various other quinoline derivatives are described in Chapter 
XV. (Uric Acid Eliminants). 

 Formaldehyde. — The strong antiseptic properties of formal- 
dehyde, have only recently been made use of in medicine, as 
the application of this substance has been hindered by its 
corrosive and toxic action. It readily polymerizes, forming 

CH . OH 

/\ 
tri-oxy-methylene, HO . CH CH . OH, which is also strongly 

antiseptic, but gives rise to bad effects when taken internally. 
Formaldehyde has long been used for the disinfection of rooms, 
for which purpose its volatility renders it eminently suitable, 
but its use as a drug depends on the manufacture of compounds 
which slowly split off formaldehyde under the influence of the'' 
secretions of the organism. 

One of the earliest compounds of this class was Glutol, ob- 
tained by the action of formaldehyde on gelatine ; other com- 
pounds of this type have been iprepared with formaldehyde 
and casein,^ and formaldehyde and nucleic acid, the latter 
compound yielding soluble alkali salts.^ The compounds of 

1 Bottinger, Annalen, 188 il877), 330 ; 208 (1881), 138 ; Ber„ 13 (1880), 
2032 ; De Jong, Rec, Trav, Chim,, 23 (1904), 136. 

2 D. B. P., 88,620. » Ibid,, 13,566. * Ibid., 139.907. 



176 



SYNTHETIC DRUGS 



formaldehyde and carbohydrates are of greater importance. 
Classen found that formaldehyde reacts with starch, dextrin, 
etc., yielding insoluble, odourless, non-irritant substances, which 
slowly split off formaldehyde, and are antiseptic without being 
poisonous.^ Soluble condensation products of dextrin and 
formaldehyde {Dextroform) can be obtained by a modification 
of this process.^ A condensation product of formaldehyde 
with lactose has, under the name of Formamintj attained great 
popularity. This substanc3 is used in the form of tablets, 
which, when allowed to dissolve in the mouth, liberate formal- 
dehyde, and so check and prevent septic conditions in the 
throat and mouth. 

Hexamecollj a condensation product of guaiacol and hexa- 
methylenetetramine, has been considered in the previous 
chapter. 

Formaldehyde reacts readily with ammonia, forming hexd- 
methylenetetr amine y {GK^^^, discovered by Butlerow ^ in 1860. 

6CH2O + 4NH3 = (CH2)eN4 + 6H2O. 

It is a basic substance, very soluble in water, and its constitu- 
tion is probably represented by the formula — 




N ^N 

\ / 

This substance has strong antiseptic properties, but its aqueous 
solutions can be taken internally without causing poisonous or 
irritant symptoms. It is largely used in medicine, under the 
names of HexaminBy Urotropin, Cystamine and Cystogen, as a 
urinary antiseptic, for which purpose it is stated to be better 
than salicylic acid or any of the older preparations. It has 



^D. R. P., 92,269, 93,111, 94,628, 99,878. 

3 Ibid., 94,282. » Butlerow, Annalen, 115 (1860), 322. 



OTHER ORGANIC ANTISEPTICS 177 



A. 




some solvent action on urio acid, buj^p is improbable that it is 
capable of dissolving uric acid to jf^ extent in the concentra- 
tions in which it can be present^v^the organism (c/. Chapter 
XV.). It is also said to be of vMe in laryngitis, pharyngitis, 
etc. The anhydromethylene-c^ic-acid — 

CHa— O- 

C— CH2— COOH 



A, 



JHa— COOH 

derivative of urotropine has been introduced under the names 
of Nev) Urotropin and HelmitoL 

A large number of other derivatives and additive products of 
hexamine have been introduced into medicine as urinary anti- 
septics. For example, Amphotropin is hexamine camphorate, 
and the additiVe compounds of hexamine with sodium acetate, 
sodium citrate, and sodium benzoate are known respectively 
as Cystopurin, Formurol, and CystazoL In the last-named, 
the antiseptic properties of the sodium benzoate are added to 
those of the hexamine. 

Tannic and Gallic Acids. — Tannic acid is distinguished by 
its astringent and styptic action, and its freedom from toxic 
effects ; gallic acid is more irritant and five times as antiseptic 

COOH 
as tannic acid.^ Gallic acid has the structure, (^ , 

HolJoH 
OH 

but that of tannic acid is not known with certainty. Its 
empirical formula is Ci4H^o09, from which it appears to be a 
dig&llic acid. 

In order to avoid the unpleasant taste of tannic acid itself, 
varipus insoluble derivatives have been prepared, which pass 
unchanged through the stomach, and are decomposed in the 
intestine, where they liberate free tannic acid. jTannigen is an 
insoluble acetyl derivative of tannic acid, soluole in alkalies.^ 
T£knn^^QXni, one of the best examples of this class, is a con- 
densation product of tannic acid and formaldehyde ' — 

^ Heinz and Liebrecht, Ber. kUn. W, (1891), 584. 

« D. R. P., 78,879 ; H. Meyer, Deut. med. W,, 31 (1894). 

»D. R. P., 88,082. 

12 



178 SYNTHETIC DRUGS 

20i4HioOg + HCHO - CH2(Ci4H^>09)2 + HjO. 

It combines the antiseptic properties of formaldehyde with the 
astringent action of tannic acid, and is used internally as an 
astringent and antidiarrhcBio ; externally it is used as an anti- 
septic for wounds, etc. 

Similar preparations of gallic acid have been devised, but the 
compounds of this acid containing bismuth are of more impor- 
tance. Bismuth has a beneficent action on wounds, causing 
the surface to dry without impairing the healing power,^ and 
therefore its insoluble compounds with antiseptic and as- 
tringent substances readily lend themselves for use as iodoform 
substitutes (c/. next chapter). 

HOv .OH 

Dermatol is basic bismuth gallate, HO-^CgHa — COOBi^ 

ho/ ^OH' 

and is a favourite iodoform substitute. 

Airol is a derivative of Dermatol, in which one of the hydroxyl 
groups attached to the bismuth is replaced by an iodine atom,^ 

.OH 

(H0),CgH2 — CO — — Bi^ . In presence of moisture, it 

liberates free iodine, and it can therefore be regarded as a true 
iodoform substitute, owing its antiseptic action to the actual 
liberation of iodine. The presence of the bismuth and gallic 
acid confers also an astringent action on this substance. It 
is used externally as an iodoform substitute (c/. Chapter XII.). 

> Steinfeld and H. Meyer, A. e, P. P., 20 (1886), 40. 
«D. R. P., 80,399. 82,593. 



CHAPTEE XII. 

HALOGEN ANTISEPTICS AND OTHER HALOGEN COMPOUNDS. 

Chlorine Compounds. 

The strong germicidal properties of chlorine and of hypo- 

chlorons acid have long been known. Bleaching powder, 

which is essentially a compound of calcium chloride and hypo- 

.0—01 
chlorite, Oa<^ , has been used extensively for many years 

as a disinfectant, for which its cheapness renders it very suit- 
able. Sodium hypochlorite, NaOCl, is readily soluble in water, 
but its caustic and irritant properties prevented its use as an 
antiseptic for the dressing of wounds. Eecently, however, it 
has been shown by Carrel and Dakin that solutions of sodium 
hypochlorite to which boric acid has been added are far less 
irritant, and very good results have been obtained with such 
solutions in the treatment of infected wounds. The name 
** EusoV* has been applied to this solution. Nevertheless, 
these solutions still possess irritant properties, and a further 
improvement in this respect was effected by substituting 
sodium bicarbonate for the boric acid. This modified form of 
Dakin's solution is prepared by the action of a solution of 
sodium carbonate and sodium bicarbonate on bleaching-powder, 
and care must be taken that it contains from 0*45 per cent, to 
0*5 per cent, of sodium hypochlorite. It has been very largely 
used with great success for the irrigation of wounds. 

More recently, organic chloramines have been introduced 
by Dakin as substitutes for sodium hypochlorite. These sub- 
stances were first discovered ^ and investigated by Chattaway 

iChattaway, J, C. S., 87 (1906), 145. 

179 12 * 



i8o SYNTHETIC DRUGS 

and are prepared by the action of hypochlorite solutions upon 
organic compounds containing the imino ( — NH — ) or amino 
( — NHg) groups, whereby chloramines containing the ( — NCI — ) 
group, and dichloramines containing the ( — NClg) group, are 
produced. Physiologically, th^fifaption resembles that of hypo- 
chlorite, but therapeutically ilbey possess^ many advantages 
over it. For example, tmfB,reia,r less irritant, and tnre stable 
solid^ which can be dissolved in water to give solutions of a 
definite strength, whereas sodium hypochlorite cannot be kept 
in the solid state, and its solutions are always of somewhat 
uncertain strength. 

The best known and most used of these chloramines is the 
substance introduced under the name of Ghlor amine T,^ It is 

CH, 
sodium p-toluenesulphonchloramide, /N and 




lOa— NClNa, SH^O, 
is prepared from |)-toluenesulphonyl chloride, a by-product 
in the manufacture of saccharin. This by treatment with 
ammonia is converted into j)-toluenesulphonamide, which . on 
warming with sodium hypochlorite solution is converted into 
Ghloramine T. 

GMg . CqS^ . BO2CI ->• OMj^ . GqH.^ . BO2 . NHj — > 

CHjj . CgH^ . SO^NCaNa. 

It is also prepared by dissolving Dichloramine T (see below) 
in hot caustic soda solution.^ This substance is also known by 
the trade name of Tolamine. 

It is a stable crystalline compound which is soluble in water, 
and has been of great value in a variety of septic conditions, 
especially in military surgery for the treatment of infected 
wounds. Its freedom from irritant properties has rendered it 
particularly useful in the treatment of injuries to the mouth 
and jaw. It is also used as a disinfectant lotion in cases of 
infectious disease such as scarlet fever, measles, etc. 

The corresponding dichloramine, j9-toluenesuIphondichlor- 

^ Dakin, Oohen, Daufresne and Kenyon, Proc, Boy, Soc., B 89 (1916), 
232; Dakin, Cohen, and Kenyon, B. M. J. (1916), 160. 
' Chattaway, loe. cit. 




HALOGEN ANTISEPTICS AND OTHER COMPOUNDS i8i 
CH3 

amide, ^ is also used as an antiseptic under the 

-NCI2, 
name of Dichloramine T, 

It is readily prepared by dissolving |)'toluenesulphonamide 
in bleaching powder solution, or by the action of hypochlorous 
acid upon Ghloramine T. 

It is used for the treatment of wounds^ in the form of a 
solution in solvents such as '' chlorcosane " (chlorinated paraffin 
wax) and chlorinated eucalyptol. Its oil solution has also 
been used as a naso-pharyngeal sterilizer in cases of menin- 
gitis, and complete sterilization of the carrier has been claimed 
by this means. 

Another dichloramine derived from j7-toluenesulphonamide 

COOH 
is |?-sulphondichloraminobenzoic acid, /\ . This 




~NCl2 

substance is known as Halazone, and is specially recommended 
for the sterilization of drinking water.^ It is prepared by 
heating ^-toluenesulphonamide with bichromate and sulphuric 
acid, whereby the methyl group is oxidized to the carboxyl 
group with formation of j7-sulphonamino-benzoio acid. This 
acid is then dissolved in caustic soda solution, and treated 
with chlorine gas in the cold to form the desired dichloramino 
acid. 

CH3 . CgH. . SO2 . NH2 -> COOH . CgH. . SO2 . NH2 -» 

COOH . CgH^ . SO, . NCI2. 

Iodine Compounds. 

Iodoform and its Substitutes. — ^Iodoform has been very 
extensively used in surgery as a dressing for wounds, as it 
seems to promote healing as well as exerting an antiseptic 
action. In laboratory experiments in vitro, iodoform has so 
slight a bactericidal power as to indicate that it would be use- 
less for such a purpose, and its antiseptic action appears to be 

^ Dakin and Dunham, Pharm, Journal, 1(K) (1918), 82. 
a/W., B. M. J. (1917), 683, 



i82 SYNTHETIC DRUGS 

due to the free iodine liberated when it comes into contact with 
fat, putrefactive material, etc. 

Iodoform is prepared according to a well-knoWn method by 
the action of free iodine on a warm mixture of acetone or 
alcohol and sodium hydtoxide or carbonate solution. In this 
process, part of the iodine is used up in forming alkaline iodide, 
from which free iodine has to be again regenerated before it 
can be used for the manufacture of a further quantity of iodo- 
form. For this reason, various electrolytic methods for pre- 
paring iodoform have been devised. One of these consists in 
electrolyzing in a current of carbon dioxide a warm solution 
of potassium iodide to which alcohol has been added.^ 

The same method can be applied to the preparation of chloro- 
form and bromoform, but in these cases the stream of carbon 
dioxide is unnecessary. Iodoform is also manufactured by 
passing ozone through a solution of potassium iodide and 
sodium carbonate in 30 per cent, alcohol, at a temperature 
of 50° C. The ozone is passed into the liquid until all the 
potassium iodide has been decomposed.^ 

Iodoform, in spite of its many valuable properties, suffers 
from some serious drawbacks, the chief of these being its 
powerful odour and the fact that it often has an irritant action 
on the skin, giving rise to a kind of eczema. It also has toxic 
properties, which sometimes give rise to definite symptoms of 
poisoning. In order to mask the odour of iodoform, many 
preparations have been introduced in which it is mixed with 
strong and pleasantly scented substances, but these need not 
be mentioned here. On the other hand, by combining iodoform 
with inodorous substances, its volatility can be lowered and its 
odour destroyed. 

For example, a compound of iodoform with hexa-methylene- 
tetramine is inodorous, and is known as iodoformin? and a 
similar compound with hexamethylene-tetramine-ethyl iodide 
was introduced under the name iodoformal,"^ but both of these 
compounds are decomposed by water into their components, 
and hence in practice they possess no advantage over a mere 
mixture. 

1 D. R. P., 29,771. ^Ibid., lt§,#13. 

^Ibid., 87,812. «7Wd„ 89,243, 



HALOGEN ANTISEPTICS AND OTHER COMPOUNDS 183 

Of far greater importance are the efforts that have been made 

to produce other insoluble compounds which should possess 

the valuable properties of iodoform in promoting the healing of 

vroundSy and have the further advantage of being less irritant 

and toxic than iodoform, and free from any powerful odour. 

Many substances have been prepared in attempting to meet 

these requirements, and these comprise derivatives of iodine as 

well as those of other halogens and of various metals such as 

bismuth. Of the various iodine derivatives, pure and simple, 

that have come into use, only one of them, io^l (tetraiodo- 

pyrrol), resembles iodoform in the fact that its action is due to 

the actual liberation of iodine. Airol, a bismuth compound, 

which also liberates free iodine, has been considered in the 

previous chapter. 

In aromatic compounds it is true that the antiseptic power is 
generally increased by the replacement of hydrogen by iodine, 
but nevertheless the latter is too firmly united to the nucleus 
to be liberated by the action of the tissues, and therefore these 
compounds cannot be compared in their action with iodoform. 
In the case of the pyrrol ring, however, the iodine is in a more 
labile state, and tetraiodo-pyrrol — 

I— C C— I 



I— C 0— I 

\/ 

NH 

resembles iodoform in its action, and has the advantage of being 
odourless and non-irritant, as well as insoluble. It is used as 
an iodoform substitute under the name of iodol, and is pre- 
pared by the action of iodine on an alkaline solution of pyrrol, 
the latter being obtained from " bone-oil." ^ 

There are, however, many other organic derivatives of iodine 
which possess antiseptic properties, and are used as iodoform 
substitutes, although their mode of action is quite different. 
For example, by the addition of a solution of iodine in potassium 
iodide to an alkaline solution of a phenol, compounds are pro- 
duced containing two atoms of iodine, one of which replaces 

1 D. B. P., 36,130, 38,423. 



i84 SYNTHETIC DRUGS 

a nuclear hydrogen atom, and the other the hydrogen of the 

hydroxy! group. By the action of sodium sulphite, the iodine 

atom can he removed from the 01 group and the mono-iodo- 

substituted phenol formed. A different type of iodophenol 

is produced by the action of iodine in potassium iodide on 

phenol-carboxylic acids in presence of an exact amount of 

alkali, whereby the COOH group is removed by loss of COj, 

and iodine enters the nucleus but not the hydroxyl group.^ 

/\COOH 
For example, ,when treated in this way, yields tri- 

OHgVOH 

iodo-meta-cresol, | | . The same product may also be 

CHgyOH 

prepared by adding a solution of iodine in potassium iodide to 
a very dilute solution of meta-cresol in alkali.^ 

The iodoxyl compounds, containing the group — 01, possess 
marked antiseptic and anti-syphilitic properties, but the iodo- 
phenols containing iodine in the nucleus do not differ very 
much from the phenols in their action, but they are sometimes 
used, as they are convenient crystalline insoluble antiseptics. 

The best known of the iodoxyl compounds is Aristolj di- 
thymol-diodide — ^ 



ICKJCHj 



;/ ^,/.^:' A I • '- 



'^ . J M • cl^ 



loAcH 

which is a favourite antiseptic, but suffers from the drawback 
of being rather unstable and expensive.^ 
Europhen — 

CH3 CgHg CgHg CH3 



01 O 

1 D. R. P., 72,996. ^Ibid., 106,504. sl6id., 49,739. 

* EiohhofE, Monatsh.f,pr. Derm. (1890), 2 ; Neisser, Berl, klin, W, (1890), 
Nr. 19, 



HALOGEN ANTISEPTICS AND OTHER COMPOUNDS 185 

is another substanoe of this type which serves as an odourless 
and non-irritant iodoform substitute.^ 

Tri-iodo-cresol, known by the fancy-name of Losophan, is 
an example of a phenolic compound in which the hydrogen 
atoms of the nucleus are replaced by iodine. These substances 
possess the antiseptic properties of phenols in an enhanced 
.degree, but they cannot be regarded as iodoform substitutes, 
as they do not possess the characteristic iodine action, and are 
also too corrosive in their action on the skin. 

Tetra-iodo-phenolphthalein has been prepared by many dif- 
ferent methods.2 Phenolphthalein itself — 

(CeH, . 0H)2-C/\C0 

O 

when taken internally has a mild purgative action, but is other- 
wise physiologically inert ; but the tetra-iodo-derivative — 

CgH4 

O 

called Nosopherij has powerful antiseptic properties. As this 
substance contains two hydroxyl groups, salts can be prepared 
with the heavy metals such as zinc, iron, mercury, and bismuth, 
but these have not come into use, although they combine the 
antiseptic action of nosophen with the useful properties of the 
metal. 
Isoform is the name that has been given to para-iodoxy-anisol, 

CH X ) ^IOq» a colourless insoluble powder that has been re- 
commended as a dry antiseptic, and which is said to be especi- 
ally valuable in the treatment of mercurial stomatitis.^ It is 

obtained by the oxidation of para-iodo-toluene, GHa \ y l, 

whereby CHa< ( ^ IClg or CH3< ^ ^ 10 is formed, either being 

easily oxidized to G^ X. V lOg-^ Commercially, it is not met 

ID. R. P., 56,830, 61,676. 

» Classen, Ber., 28 (1896), 1606; D. R. P., 86,930, 86,069, 88,390; Kalle 
& Co., D. R. P., 143,696. 

'Siebert, Deut, med. W*y 7 (1907), 256. *D. R. P., 161,726. 



i86 SYNTHETIC DRUGS 

with in the pure state, but owing to its explosive nature is 
mixed with calcium phosphate or glycerol. 

Sozoiodol, CgH2l2(OH)(S08H),i probably owes its antiseptic 
action partly to its strongly acid character. Its zinc and 
mercury salts are useful preparations for the administration of 
these metals. 

Lcretin is iodo-hydroxy-quinoline sulphonic acid — 

SOoH 

N OH 

prepared by Claus by the sulphonation of hydroxy-quinoline 
with fuming sulphuric acid, and treating the reaction-product 
with iodine.^ This substance is said to be an iodoform sub- 
stitute free from unpleasant effects. Its sodium salt has been 
used in tuberculosis under the name of Griserin,^ Other simi- 
larly constituted compounds with the same kind of action have 
been prepared, and iodo-chlor-hydroxy-quinoline * has been in- 
troduced as a non-poisonous iodoform substitute under the name 
of Vioform. 

Substitutes for Alkaline Iodides. — Another important class 
of iodine compounds includes those substances which have been 
prepared with the object of producing substitutes for the alka- 
line iodides. The latter are largely used in medicine, but are 
liable to cause unpleasant symptoms, to which the term " iodism " 
is given, and for this reason a very large number of drugs have 
been introduced with the object of furnishing substances which 
should possess the therapeutic value of the alkaline iodides 
without giving rise to the symptoms of iodism. 

Iodoform has been used internally, being for the most part 
converted by the organism into alkaline iodides, but it has no real 
value in this respect. Compounds of iodine (and of bromine) 
with fats which gradually split off their iodine appear to be very 
good substitutes for the alkaline iodides, compared with which 
they are said to possess many advantages.^ 

ID. R. P., 45,226. ^Ibid., 72,942. 

^Apoth, Ztg. (1904), 908. *D. R. P., 117,767. 

» H. Winternitz, BeuL med, TF., 23 (1897). 



HALOGEN ANTISEPTICS AND OTHER COMPOUNDS 187 

lodipin is one of the best known substances of this type, and 
is a combination of iodine and sesame-oil.^ 

lothion is di-iodo-hydroxypropane, CgHglgOH, and is used in 
the form of ointments as a substitute for tincture of iodine. 

lodival is mon-iodo-isovaleryl-urea — 



CH3 



\0H— cm— CO— NH— CO— NHj, 



ch/ 

and is administered internally as a substitute for iodine and the 
iodides. It is said to be specially useful in nervous diseases, 
and in syphilis. 

CH3O 

Para-iodo-guaiacol,^ H0< ( y — I, is decomposed into its 
components in the intestine, and has been recommended as a 
substitute for the iodides. 

The thyroid gland contains iodine in organic combination, 
and various attempts have been made to prepare a similar 
substance to the so-called " iodo-thyrine " by combining iodine 
with proteins. The products thus obtained do not resemble 
iodo-thyrine in their physiological effects, but they form useful 
substitutes for the alkaline iodides. Compounds of iodine with 
proteins are readily obtained by the addition of iodine in potas- 
sium iodide solution to aqueous protein solutions, or by adding 
finely powdered iodine to warm aqueous solutions, and coagu- 
lating the product with acetic acid.^ One of the best known 
compounds of this type is lodoglidine, a compound of iodine 
with gliadin, the vegetable protein obtained from wheat. It 
behaves in a similar manner to potassium iodide, but is said 
also to increase the metabolism, thus resembling iodo-thyrine 
in this respect.* Another compound of iodine and protein is 
lodalbin, which is also used as a substitute for the alkaline 
iodides. 

Bbominb Derivatives. 

As in the case of iodine, the entrance of chlorine or bromine 
into aromatic compounds increases their antiseptic power, but 

1 Merck, D. R. P., 169,748. » Ch&miker Zeitg., 31 (1907), 175. 

•Hopkins and Brook, Jowrn, of Physiol., 22 (1897), 184. 
*DeuL med. W., 37 (1907), 1490. 



i88 SYNTHETIC DRUGS 

the chloro- and bromo-phenols have so strong an irritant action 
that derivatives of that type have found no therapeutic applica- 
tion. 

On the other hand, the alkaline bromides are of very great 
medicinal value, being especially important in the treatment of 
certain nervous disorders. Potassium bromide has some draw- 
backs precisely similar to those attending the use of potassium 
iodide, and so efforts have been made to find substitutes which 
will possess the useful sedative properties of potassium bromide 
without its drawbacks. 

The substances here described are therefore not antiseptics, 
but are nervous sedatives and mild hypnotics. They are in- 
cluded in this chapter on account of their close chemical relation- 
ship to the iodine compounds described in the previous section, 
though they are therapeutically related to the hypnotics described 
in Chapter IV. 

Bromipin is analogous to iodipin, and is said to be a valuable 
substitute for potassium bromide. 

CH3V 
Valerobroviine, ^CH — CHBr — COONa, is said to be free 

ch/ 

from the drawbacks of potassium bromide, while retaining its 
sedative properties. It is also said to derive a sedative action 
from the presence of the valerianic acid grouping, but this 
seems doubtful. It is obtained by the action of bromine on 
valerianic acid, whereby bromo-valerianic bromide is obtained, 
which is then hydrolyzed with water and neutralized, giving 
Valerobromine — 

^\CH— CH2— CO . OH -> '^CH— CHBr— CO— BE 
CHg^ CH3/ 

CH^ 

''>CH— CHBr— CO . ONa 
CH3/ 

Other derivatives of a-bromoisovalerianio acid which are used 
as nervous sedatives are its ester with borneol, 

C^HgBr — C00CiqHi7, and its urea derivative, 
'\CH— CHBr— CO— NH— GO— NH,. 



CH3 



/ -"»• 



HALOGEN ANTISEPTICS AND OTHER COMPOUNDS 189 

The former is known as Brovalol and EubornyL The latter, 
which is exactly analogous to lodival in constitution, is known 
by the names of Bromurul and Dormigene, 

Another bromine derivative of urea which is used as a safe 
hypnotic is Adalin} bromdiethylacetylurea, 

'^CBr . CO . NH . CO . NHo. 
C2H/ 

In this compound, the mild hypnotic action of the 

— CBr.CO.NH.CO.NH2 

group is probably enhanced by the presence of the two ethyl 
groups united to it (c/. Chapter IV.). 

Bromoglidine is a compound of wheat protein with btomine, 
and Bromalbin is another bromine derivative of protein. Both 
are used as substitutes for the alkaline bromides, and they are 
respectively analogous to lodoglidine and lodalbin, 

^E. P., 2888 (1910). 



CHAPTER XIII. 

INORGANIC ANTISEPTICS AND METALLIC COMPOUNDS. 

Most of the non-metallic inorganic antiseptics, like the chlorine 
compounds described in the previous chapter, owe their antiseptic 
properties to their oxidizing power. Practically the only ex- 
ception is boric acid, H3BO3, which is a very weak antiseptic. 

Hydrogen peroxide, H2O2, is a very useful antiseptic and dis- 
infectant. In the presence of wounds and septic conditions it 
is decomposed into water and nascent oxygen, and has the great 
advantage of being odourless, non-poisonous, and almost free 
from irritant action. Other advantages of hydrogen peroxide 
are that it does not precipitate protein, and leaves only water 
when it has exerted all its antiseptic action. 

A 30 per cent, neutral solution of hydrogen peroxide is known 
as Perhydrol. The peroxides of the alkaline-earth metals may 
be regarded as derivatives of hydrogen peroxide, and Magnesium- 
Perhydrol or Biogen (a mixture of MgO and Mg02) and Zinc- 
Perhydrol or Ektogen (a mixture of ZnO and ZnOg) are used as 
antiseptics ; the former is for internal and the latter for external 
use. 

Another compound of this type which may be regarded 
as a derivative of hydrogen peroxide is sodium perborate, 
NaB03,4H20, known as Perborax. 

Various organic derivatives of hydrogen peroxide have been 
prepared, but as they owe their antiseptic properties solely to 
the liberated oxygen, they have not been considered in the 
chapters devoted to the true organic antiseptics. An example 
of this type is benzoyl-acetyl hydrogen peroxide — 

OeHg . COv 
CgHfi . CO— 0—0— CO . CH3 or >0 = O 

CH3 . CO^ 
known as Acetpzone. 

190 



INORGANIC ANTISEPTICS AND METALLIC COMPOUNDS 191 

For a similar reason, various metallic salts of organic acids 
are also included in this chapter, rather than in that on the 
organic antiseptics, as their action depends on the metal and 
not on the organic acid radicle. 

Derivatives of Mercury. — Mercury compounds are used very 
considerably as antiseptics, and also in the treatment of syphilis. 
The part played by antiseptics in the specific treatment of 
protozoal diseases was discussed in Chapter XI., and in this 
section a description is given of the various preparations of 
mercury, and the raison d'etre of their existence. 

As antiseptics, mercury salts suffer from the drawback that 
metallic instruments cannot be immersed in them, and for the 
treatment of syphilis, their corrosive, irritant and toxic nature 
is a serious disadvantage. For this reason, many efforts have 
been made to prepare soluble mercury salts which can be injected 
without giving rise to the bad effects of the simple soluble salts, 
such as the chloride. In another direction, attempts have been 
made to obtain soluble mercuric salts in which the electro- 
negative character of the mercury is masked, so that solutions 
may be used for the sterilization of metallic instruments without 
the former being reduced with liberation of metallic mercury. 
Another drawback of mercuric chloride is the fact that it is not 
very soluble, and only dissolves slowly. 

A method of administering mercury which has found a good 
deal of favour is by intramuscular injections of calomel (mercur- 
ous chloride, HggClg), and of metallic mercury. For example, 
" Lambkin's Cream " (No. 1) consists of an emulsion of 5 
grams calomel and 20 grams " creocamph " made up to 100 c.c. 
with palmitine or carbolized liquid paraffin. The " creocamph " 
is a mixture of equal parts creosote and camphoric acid, and is 
used to minimize pain at the site of the injection. This cream 
(No. 1) is followed by No. 2 which resembles it except that the 
5 grams of calomel are replaced by 10 grams of free mercury. 

A stronger medium is " Grey Oil " which contains 40 grams 
of metallic mercury, 26 grams of lanoline, and 60 grams of 
vaseline, this being 40 grams of mercury to 100 c.c. compared 
with 20 grams to 100 c.c. in the case of Lambkin's Cream, 
No. 2. 

Sometimes the older method of using mercurial ointment (the 






192 SYNTHETIC DRUGS 

oleate or the free metal) is preferred, in spite of the indefinite 
amount of mercury that is absorbed through the skin, as com- 
pared with the exact amount administered by intra-muscular 
injection. Colloidal metallic mercury^ has been tried as an 
injection medium, and various phenolic derivatives of mercury 
have been prepared,^ such as the mercury salts of phenol, 
naphthol, resorcinol, and tribromophenol, but these latter do 
not appear to be suitable for injection. The dimethyl, diethyl, 
and diphenyl derivatives of mercury are too dangerously toxic 
to be of any therapeutic value. Most satisfactory results 
seem to have been obtained with mercury derivatives of acid- 
amides, and amino-acids. Mercury derivatives of formamide, 
(H . CO . NH — )2Hg, and of succinimide as well as those 



CjH,/' \n jHg, 



^cq/ 



of asparagine, [NHg . CO— CH(NH2) . COOJgHg, and alanine, 
[CHj— CH(NH2)— COOJgHg, have been prepared. Of these, 
mercury succinimide has been used in medicine under the name 
of Hydrargol, 

Good results are said to have been obtained with secondary 

CO— Ov 

mercury salicylate, G^'H.^^ y Hg, a substance from which 

the mercury cannot be precipitated with H^S. Although this 
compound is itself insoluble in water, it yields soluble double 
salts with the alkali chlorides. Mercurous tartrate, prepared 
by Lustgarten, is decomposed by the intestinal alkali, with 
liberation of finely divided mercury. 

Of the various injection media that have been tried, the 
best results, so far, appear to have been obtained with various 
protein preparations. Some of these, obtained from glue, are 
soluble in water in any quantity, and are not precipitated by 
protein, nor acted on by alkalies with liberation of mercury (c/. 
Silver). 

The mercury salt of para-phenol-sulphonic acid, known as 

^ Lottermoser, Joum,prakt Chem,, 57 (1898), 484. 
«D. R. P., 48.fi39. 



INORGANIC ANTISEPTICS AND METALLIC COMPOUNDS 193 

Hydrargyrol, ("EiO^ ^SOa — — )2Hg, is said not to precipi- 
tate proteins, and not to attack metallic instruments. A doable 
salt of this substance and ammonium tartrate is more stable, 
CiaHioOgSaHg, 4[C4H40e(NHj2] + SHgO,! and has been intro- 
duced into practice under the name of Asterol, It is soluble in 
water, giving a clear neutral solution, frOm which HgS does 
not precipitate HgS. It is stated that aqueous solutions of 
asterol do not precipitate albumen,^ and though the bactericidal 
action is only about half that of mercuric chloride, the solutions 
have the advantage of not losing any of their power in protein 
fluids, and of penetrating further into the tissues than solutions 
of sublimate. Asterol does not iMtiiterize wound surfaces, and 
does not injure metallic ius>rtiments, and on account of these 
numerous advantages it is recommended for general surgical 
use. 

Thymegol is a snbstance of a similar type to Hydrargyrol, and 
is the mercury potassium salt of thymol j7-sulphonic acid. 

Similar preparations have been obtained by the action of 
mercuric oxide on alkaline solutions of phenol-(2tsulphonic acid 
in molecular proportions.* They are termed Hermophenylf and 
are soluble in five parts water. Potassium mercury hyposul- 
phite is also said to be non-irritant and easUy soluble.^ 

Hydrargotin is mercury tannate, and Toxynone is sodium 
m-acetylaminomercuribenzoate, 

HO— Hg— CeH3(NH . CO . CH,)(COONa). 

Soluble mercury preparations which do not attack metallic 
objects have long been used in this country in the form of 
potassium mercury iodide, to which alkaline carbonate has been 
added. Similar compounds have been introduced in Germany 
by adding mercuric cyanide, cyanate, or j^-phenol-sulphonate to 
alkaline carbonates.^ 

Silver. — Silver nitrate, besides its well-known caustic action, 
possesses strong bactericidal properties^ but as it is precipitated 
both by proteins and by chlorides, its use is confined to the 
surface of the body. It would be desirable to obtain a com- 
pound of silver which, while retaining its bactericidal proper- 

1 D. R. P., 167,663. aSteinmann, Ber. klin. TT., U (1899), 229. 

> Lumi^re and Ohevotier, C. jB., 132 (1901), 145. 

« Dreger, A, e. P. P., 32 (1893), 466. » D. R. P., 104,904, 121,666. 

13 



ig4 SYNTHETIC DRUGS 

ties, should be free from the oaostic action of silver nitr«ite» and 
not be precipitated by chlorides or proteins. Brief mention 
4ieed only be made of ooUoidal silver chloride and colloidal 
silver solutions, which were at one time in great vogue for dis- 
infection of the tissues by intravenous injection. Such methods 
are useless, as the damage done to the tissues is greater than to 
the bacteria, and treatment of this kind is only justifiable for 
local infections (c/. following chapter). 

These colloidal solutions, as also solutions of silver phosphate 
in ethylene-diamine, fulfil n)ost of the chemical requirements 
outlined above, but they suffer from various drawbacks which 
have prevented their general application. The compound of 

CHa— NHa 
silver nitrate and ethylene-diamine, I , however, is 

OHg— NHg 

used as a substitute for silver nitrate under the name Argen- 
tamin. 

As in the case of mercury, better results have been obtained with 
protein compounds. Argonin is a compound of silver and casein, 
but is difficultly soluble in water and sensitive to light. Pro- 
targol is a compound of this type which has a higher percentage 
of silver, is free from caustic effects, does not precipitate chlorides, 
and has the bactericidal effects of silver. To prepare it, a peptone 
solution is precipitated with silver nitrate solution or shaken with 
moist silver oxide, and the insoluble compound thus obtained, 
digested with protalbumose. Soluble protargol is formed in this 
way, and is separated from the solution by evaporation in vacuo. 
Similar compounds can be obtained from plant globulins, and 
the corresponding compounds have also been obtained from 
mercury, iron, copper, lead, zinc, and bismuth.^ Other silver 
albumin compounds have been obtained from gelatoses (hydro- 
lytic products from glue).^ Albargin, a pOwder readily soluble 
in water and of neutral reaction, is a substance of this type. It 
is recommended in various septic conditions as a non-irritant 
antiseptic. 

Protosil is another silver protein compound, very soluble in 
water, and is not precipitated by chlorides or by protein. It 
contains about 20 per cent, of silver. 

ip. R. P., 118,353, 118,496. ^Jbid.y 141,967, 146,792, 146,793. 



INORGANIC ANTISEPTICS AND METALLIC COMPOUNDS 195 

Nargol is a silver nucleinate, soluble in warm water, and 
isontains about 10 per oent. of silver. 

Zinc. — Many salts of zinc possess astringent and antiseptic 
properties. A soluble zinc salt, jrecommended for' various dif- 
ferent complaints as a non-irritant antiseptic, is Nizin^^ a zinc 
salt of sulphanUic acid, (NHg — OgH^ — S0g)2Zn, dHgO. 

Zinc perhydrol combines the antiseptic properties of hydrogen 
peroxide with the astringent properties of zinc, and has already 
been mentioned (p. 190). 

Aluminium. — The astringent properties of ordinary alum are 
well known. The aluminium salt of fi naphthol-disulphonic 
acid, [GioH50H(S03)2]3Al2, is an example of the various organic 
alukninium salts that have been prepared. It is known as 
Alumnol,^ and is recommended as a mild antiseptic, etc. 

Iron. — ^Ferric salts resemble those of aluminium in many of 
their properties, and they are used as astringents and styptics. 
For use as a styptic, a double compound of ferric chloride and 
antipyrine has been introduced under the name of Ferripyriuy 
but it has no advantages compared with ferric chloride itself. 

The chief therapeutic use of iron is, however, in anaemia and 
chlorosis. For this purpose, the ferrous salts are usually pre- 
ferred, as they do not have so great a caustic action as the ferric, 
and hence do not disturb the stomach so much. The unpleasant 
by-efifects of iron on the teeth and stomach have led to many 
attempts at obtaining compounds which should be free from 
these disadvantages. 

By the reduction of hasmoglobin, Robert obtained a substance, 
hcBfnoly which contains the iron in the same form as haBmoglobin, 
and Bunge obtained from egg-yolk a substance from which the 
iron could not be precipitated by ammonium sulphide.' This 
substance was termed hcBmatogen by Bunge, and a similar sub- 
stance has been isolated from the liver.^ A synthetic albuminate 
of iron was obtained by Schmiedeberg,'^ but this differs from 
Bunge's hsematogen in certain respects. Various other albumin- 
ates of iron have been prepared, and many of these^ as well as 
some of the foregoing substances, have been placed upon the 

^Apotheker Zeitung (1908), 215. 

«D. R. P., 74,209 ; Ber, klin, W., 46 (1892). 

* Zeit. physiol, Chem., 9 (1884), 49. 

* IWd., 10 (1886), 463. M. «. P. P., 35 (1894), 101. 

13 * 



igfi SYNTHETIC DRUGS 

mai^et {Hamol, Eamatogent eto.). None of these organic com- 
pounds are any more powerful agents in the treatment of ansamia 
than the simple inorganic salts, their advantage being simply 
that they are less irritant to the gastro-intestinal tract. 

Eecently, iron has been used with success in the treatment of 
syphilis (c/. " Arsenic Compounds," Chapter XTV.). The sub- 
stance which has been found most useful in this respect is ferric 
sulphanilate, Pe(SO,<(^~^NH2)8, known as Ferrivine} It is 
a stable substance readily soluble in water. 

Compounds of arsenic and antimony, as well as certain 
bismuth preparations, are dealt with elsewhere. (Chapter XIV., 
and pp. 128, 178). 

^ McDonagh, Lancet (1916), 239. 



\ 



CHAPTER XIV. 

ARSENIC AND ANTIMONY CX)JiPOUNDS. 

Introduction. — ^ArseniouB oxide and the salts derived from it 
have for many years been used as tonics and in the treatment of 
ansBmia, while the irritant properties of antimony have long been 
made use of in potassium antimonyl-tartrate (tartar emetic). In 
this chapter, however, it is proposed to deal mainly with a 
modem development of the therapeutics of arsenic and anti- 
mony, namely, with their use in the treatment of diseases of 
protozoal origin, such as trypanosomiasis (sleeping sickness), 
syphilis, etc. This subject offers a very good example of the 
application of Ehrlich's views on chemico-therapy and the 
action of chemical specifics to which reference has already been 
made in Chapter XI. (pp. 170-173). 

For the treatment of these diseases, the organic derivatives of 
arsenic, especially those containing an aromatic nudeus, have 
proved the most useful. In the case of antimony, its close 
resemblance to arsenic indicates the probability of its useful 
application in the same way, but up to the present, antimony 
compounds analogous to the most successful arsenic compounds 
have not been used. 

Within recent years it has been shown that the "sleeping 
sickness " of tropical Africa is caused by a protozoal parasite, 
the Trypanosoma gamhiense, and this disease was found to react 
to various specifics, such as arsenic, although unfortunately 
their clinical use has not been completely successful. It was 
found that certain organic preparations, of which atoxyl was 
one of the first to be extensively tried, appeared to be more 
satisfactory than the older inorganic preparations, such as 
Fowler's solution (potassium arsenite). Nevertheless atoxyl is 
devoid of action on the trypanosomes in vitro, and it can only 
become specific for them when it undergoes some change in the 

197 



IgS SYNTHETIC DRUOS 

body. Most of the atoxyl passes through the body unchanged, 
but the small portion which becomes changed is apparently 
capable of destroying a large proportion of the parasites. Prob- 
ably the arsenic in this portion is changed into some compound 
of an unknown nature, the same or a similar compound being 
also formed from part of the arsenic in inorganic preparations. 
Although the active therapeutic agent is therefore probably the 
arsenic content, it is no doubt true that atoxyl possesses ad- 
vantages over inorganic preparations by virtue of its physical 
properties, such as solubility. It is possible that it is able to 
penetrate into tissues which cannot be readily reached by in- 
organic arsenic. 

Organic arsenic preparations of this type have also been used 
for the treatment of syphilis, but atoxyl does not appear to be 
so useful as mercury in this respect, although excellent results 
have been obtained with some of the newer preparations such 
as Salvarsan and its derivatives, especially when used in con- 
junction with mercury. 

Antimony possesses somewhat similar pharmacological pro- 
perties to arsenic, and on investigation antimony^ was found 
to have an even stronger trypanocidal action than arsenic, but 
its inorganic preparations labour under the disadvantage of 
being strongly irritant, while organic preparations of antimony 
analogous to atoxyl are difficult to prepare, and are not effective 
therapeutically. 

Bismuth also has a powerful trypanocidal action, but it 
appears to be too toxic to the host to be of clinical value. All 
three metals, arsenic, antimony, and bismuth, appear to be fatal 
to trypanosomes in concentrations of one in two hundred thousand 
or even less, but Gushny has shown that a concentration of 
arsenic of one in three thousand four hundred is necessary to 
kill the harmless non-parasitic protozoa, such as Paramoscium 
and Golipidium, while still stronger solutions of antimony and 
bismuth, namely ^jf and /^ respectively, were necessary to 
effect the same result. These substances therefore appear to 
be true specifics against the trypanosomes, in the same way 
as quinine is a specific against the malaria organism. 

^ Cusbny, loc, eit. ; Plimmer and Thomson, Proe, Roy, Soc,, B 80 (1908), 
1477. 



ARSENIC AND ANTIMONY COMPOUNDS igg 

Some varieties of trypanosomes seem to be more sensitive 
to a given drug than others, and it therefore is desirable to use 
as many different specifics as possible in order that the parasites 
which resist one drug may be destroyed by another. It has 
also been established that the trypanosomes rapidly acquire 
a tolerance for these drugs, and therefore it is necessary to use 
large doses at the commencement of the treatment. 
. Arsenic Compounds. — As was stated above, it seems highly 
probable that atoxyl — 

O 



NaO— As— OH 




does not of itself exert a trypanocidal action, but that it gives 
rise to other substances which have this specific property. This 
problem has been the subject of extended investigations by 
Ehrlich and others,^ but the question still remains to be defin- 
itely settled. Atoxyl was first thought to be an anilide of 
arsenic acid, CgHg — NH — AsO(OH)2, but it was shown by 
Ehrlich and Bertheim to be a sodium salt of para-amino- 
phenyl-arsenic acid, NHj^ — C^H^ — AsO(OH)2, an observation of 
very great importance, as it opened up the way for the prepara- 
tion of a series of different compounds, by which means it was 
hoped to obtain compounds of a lower toxicity to the host 
(slightly organotropic) and a higher toxicity to the parasites 
(highly parasitotropic). For example, the amino-group may be 
acetylated, benzoylated, etc., or replaced by halogen, hydroxyl, or 
other groups by means of the diazo reaction, whilst by starting 
with substituted amines instead of aniline, derivatives can be 
prepared containing groups of the types — NHE and — NEg, 
instead of NHg. Of the derivatives thus obtained, some are ^ 
and some 60 or 70 times as toxic as atoxyl. The entrance of a 
sulphonic acid group in the molecule yielded a substance the 
toxicity of which is of the Same order as sodium chloride, but it 

^ A jBfeneral aocount has been given by Ehrlich, Ber., 42 (1909), 17-47. 



200 SYNTHETIC DRUGS 

is also quite inert towards the parasites.^ This is in accordance 
with the general physiological inertia of the sulphonic acids. 
The acetyl derivative— 

.OH 
CH, . CO . NH— CgH^— AsOC 

\ONa 

which is known as arsacetin, has certain marked advantages 
compared with atoxyl, being more stable and less toxic to some 
animals, while equally toxic to the parasites. Other acid groups 
have no advantage over acetyl, and with increasing length of 
the side chain the toxicity becomes far greater. 

In order to make a decided advance, it is necessary to gain 
some idea of how atoxyl and its derivatives act in the animal 
body, as it would obviously be an advantage to use a substance 
as nearly as possible identical with the product of the meta- 
bolism of the body. It is found that arsenious oxide, certain 
triphenylmethane dyes, etc., can kill parasites in blood serum 
in vitro, but that atoxyl and its derivatives do not, though in 
the body they exert a trypanocidal effect in very high dilutions, 
such as xWinnr* ^^<^ difference between action in vitro and 
in vivo may be explained by various different hypotheses, such 
as — 

(1) Atoxyl may be decomposed in the body into aniline and 
arsenic acid, the effect on the parasites being due to the in- 
organic arsenic. 

(2) According to Uhlenhuth and Woithe, atoxyl and com- 
pounds of a similar type may stimulate the cells to the pr o- 
duction of derivatives (amboceptors) which kill the parasit^fljj^ 

(3) The body may produce new products of a synthetic typ^ 
leading to the production of more active compounds. 

The first of these hypotheses is the simplest, and is in 
accordance with many of the observed facts, but its probability 
is weakened by the fact that no arsenic acid is excreted, and 
preparations have been obtained which are from ten to twenty 
times as active as inorganic arsenic. We have no knowledge 
of any actual facts in support of the second theory, and with 
regard to the third, it seems probable that some new highly 
active compounds are produced, but Ehrlich considers that such 

^ See also Ehrlich, loc, cit. 



ARSENIC AND ANTIMONY COMPOUNDS 



aot 



products of metabolism are simpler than the original compounds, 
and are not very complex synthetic bodies. 

Some significant facts have been brought to light which 
seem to indicate something of the nature of these metabolic 
changes. For example, there seems to be a close connection 
between the therapeutic efficiency of atoxyl and the resistance 
offered to it by the organism. Thus, a mouse which can readily 
tolerate yvtt ^ ^^ better influenced therapeutically by this dose 
than is an average mouse which can only stand ^^ by that 
dose. One which was very sensitive and was poisoned by y^, 
showed a very marked tr3rpanocidal effect. This seems to in- 
dicate that the organism changes atoxyl into a more toxic 
substance, which also acts very strongly on the parasites. A 
change of this kind seems probably to be connected with the 
reduction of the arsenic from the pentavalent to the trivalent 
state. 

Atoxyl, on reduction, gives |7-aminophenyl-arsenious oxide, 

NH2< ^ ^ AsO, and with stronger reducing agents jj-diamino- 

arsenobenzene, NH2< ^^ ^ As = As ^^ ^ NHg. The reduction 
products of this type are generally more toxic and more active 
against trypanosomes than the corresponding derivatives con- 
taining pentavalent arsenic. The following table shows the 
dilutions at which one cubic centimetre will kill a mouse weigh- 
ing twenty grams : — 



Group in para position to 
Arsenic 


Form in which Arsenic is Present. 


V /OH 
Rr-AsO^ 

^ONa 


m 
R~A5 = 


m m 
R--As= A*-R 


— NH- 

—OH 

— NH— CHa— COOH 


1:200 

1:76 

1:20 


1 : 16,000 
1 : 18,000 
1 : 1,000 


1:6.000 
1 : 1,000 
1: 70 



These reduction products show a very marked trypanoci- 
dal action, even in vitro. ^-Hydroxy-phenyl-arsenious oxide, 
H0< ^ ^ As = 0, is the strongest, and in a dilution of one in ten 
million kills trypanosomes in one hour. When it is realized that 



a<A SYNTHETIC DRUGS 

atoxyl does not kill trypanosomes even in five per cent, solution, 
and that the hydroxy compound, H0< >A80(0H)(0Na), 
does not do so in one or two per cent, solutions, it will be seen 
what an enormous change is produced by reduction. This is an 
example of the increased toxicity of unsaturated compounds {e.g, 
carbon monoxide, hydrocyanic acid, acrolein, etc., cf. Chapter 
II.). The increased trypanocidal action in vitro is accompanied 
by an increased action in vivo. One cubic centimetre of a one 
in forty thousand solution of j>-hydroxyphenyl-arsenious oxide 
caused the parasites to vanish from the blood of a mouse and for 
it to remain free for seven days. In the other members of the 
series, action in vivo is parallel to action in vitro, and therefore it 
indicates that the action of the derivatives of phenyl-arsinic acid 
is due to a reduction process, and indeed most of the evidence 
from all sides points to the probability of the trypanocidal action 
of arsenic and antimony being dependent on the presence of these 
elements in the trivalent state. 

Some of these trivalent aromatic arsenic compounds are 
now extensively usM in therapeutics. These are of the type 
R — As = As — R, rather than of the type R — As = 0, and are 
distinguished by their comparatively low toxicity. The reduction 

product of atoxyl itself, NH2< ( ) >As = As ^^ ^ ^NHg, has very 
high trypanocidal powers, but the compounds that have had 
the greatest success are dihydroxy-diamino-arsenobenzene, 

HQ ^ ) >As = As ^ X ^H, and its derivatives, and the reduc- 

NHg NH2 

tion product from phenylglycine-arsenic acid — 

(HO)2AsO . CfiH^— NH— CH2 . COOH, 
namely, 

HOOC— CHg— NH— <~>As = As< >NH . CHa— COOH. 
These compounds will be discussed in the next section. 

The aliphatic arsenic compounds are, at the present day, of 
no very great therapeutic importance. Cacodyl — 



>A8— As( 
CH3/ \CH 



8 

is poisonous, but the very soluble cacodylic acid, (CH3)2 = 



ARSENIC AND ANTIMONY COMPOUNDS ioi 

As^ is comparatively harmless and inert. By reason of 

their excessive stability, its salts do not show a strong enough 
arsenical e£Eect, and therefore do not find any therapeutic appli; 
cation. The same applies to " new "-cacodyl {ArrhenaT)^ which 
is monomethyl-arsinic acid, CHg — AsO(OH)a, all these ali- 
phatic compounds having been practically superseded by the 
aromatic. 

An account of most of these aliphatic arsenic compounds, 
and of the earlier aromatic ones, is given by Martindale in a 
paper communicated to the International Congress of Applied 
Chemistry, London, 1909. Section VIII. B, p. 28. 

Guaiacol cacodylate, (CH3)2AsO . O . CgH^ . OCH„ HgO, is 
known as Cacodyliacol (p. 167). 

Aromatic Arsenic Compounds. — Atoxyl was the first aro- 
matic arsenic compound to attain an extended use in thera- 
peutics, and it is still the best known. By heating aniline 
arsenate, B^champ^ in 1863 obtained a substance which he 
took to be the anilide of arsenic acid, C^Hg — NH — AsO(OH)2, 
and described the sodium, potassium, barium, and silver salts. 
A sodium derivative of this substance was introduced into thera- 
peutics under the name of atoxyl, and its correct empirical 
formula was established by Foumeau,^ who attributed to it the 

.OH 
structure CgHg — NH — As = .It is, however, a neutral 

\ONa 

substance, and the sodium-free product obtained from it was 
found to be acid, and to be identical with the product obtained by 
B^champ.^ It seemed unlikely that this compound, CgHgOjNAs, 
was really an anilide, and Ehrlich and Bertheim were able to 
show conclusively that it was para-amino-phenyl-arsinic acid, 
having the structure, 

.OH 

NH,<^As = O. 

\0H 

^ B^hamp, C. JR., 56 (1868), 1173. 

^Fourneau, Joum. Pkarm. Chim., 6 Series, 25 (1907), 382. 

s Ehrlich and Bertheim, Ber., 40 (1907), 8292. 



ao4 SYNTHETIC DRUGS 

•a 

The following were the chief reasons in support of this 
view : — 

(1) Atoxyl cannot be hydrolyzed into arsenic acid and 
aniline by any of the ordinary agents used to hydrolyze 
anilides. 

(2) It contains a primary amino group, which is easily 
diazotized and coupled with phenols and amines. It is readily 
acetylated, yielding a stable acetyl derivative. 

(3) Atoxyl corresponds in its properties with the arylarsonic 
acids of the type previously described by Michaelis and Beese. 

(4) Hydriodic acid reacts with atoxyl, replacing the arsenic 
group by iodine with formation of para-iodo-anUine, NHg ^ ^ I, 
thus proving that the arsenic and the amino group are in the 
para position to each other. 

Atoxyl is prepared by heating arsenic acid with an excess of 
aniline at 180°-190'', or by heating aniline with aniline arsenate. 
The sodium salt is then obtained by extracting with sodium car- 
bonate and recrystallizing. The acid is often known as arsanilic 
acid, and its sodium salt as sodium arsanilate, by analogy to 

sulphannic acid, NHa< >SOa— OH. 

These terms, on account of their convenience, will hereafter 
be used to denote these compounds. 

The sodium salt of this acid contains water of crystallization, 
the amount varying somewhat in the different commercial 
products. ^* Soamin** is the name given to a pure product of 
sodium arsanilate crystallized with five molecules of water. 
Other commercial products of this salt are known as Arsamin, 
Atoxylf etc. These are used for the treatment of sleeping 
sickness, syphilis, and other diseases of protozoal origin, but 
unless they are used with caution, unpleasant and even 
dangerous by-effects, of which blindness is one of the worst, 
may arise. 

^OH 

The acetyl derivative, GH^ . CO— NH< >As = O, SHgO, is 

\0Na 
said to be less toxic to many animals than atoxyl itself, and has 
the advantage of being more stable, so that its solutions can 
be sterilized by boiling. It is known as Arsacetin or Acetyl- 



ARSENIC AND ANTIMONY COMPOUNDS 205 

atoxyl, and the acid is readily prepared by the action of acetic 
anhydride on arsanilic acid. Arsacetin is then obtained by 
neutralizing with soda. 

Ortho-toluidine yields derivatives exactly analogous to those 
obtained from aniline. For example, 2-amino-tolyl-5 arsinic 
acid — 




HO— As— OH 

II 
O 

is obtained by heating o-toluidine arsenate with twice its weight 
of o-toluidine at 180''-185''. The sodium salt is then obtained 
by treatment with sodium carbonate.^ 

The free acid can be acetylated, and the acetyl-compound 

/OH 
yields a sodium salt, CH3— CO— NH^^^AsO^T analogous 

to arsacetin, and known by the trade name of " Orsvdan" It 
is soluble in two and a half parts of water at body temperature, 
and resembles arsacetin in its action, being used in the same 
way for protozoal diseases. 
jBi8-2-amino-tolyl-5 arsinic acid — 

OH 
CH3 I CH3 

NH2<^-A8-<3NH3 

II 
O 

is obtained as a by-product of the action of o-toluidine on 
o-toluidine arsenate, and it also yields the corresponding sym- 
metrical diacetyl derivative by treatment with acetic anhydride.^ 
In the same way, &i«-^-aminophenyl-arsinio acid is obtained as a 
by-product in the preparation of arsanilic acid, and this com- 
pound also yidds a diacetyl derivative. By the preparation of 
the following compounds : — • • 



•• 



1 Wellcome and Pyman, English Patent (1908), 855. 
<Fyman and Reynolds, J. C. 8., 93 (1908), 1180. 



206 



SYNTHETIC DRUGS 



NH2 



Asi 



3 



CQ 



l80(0H)j AbO(OH)j 

2-amino-tolyl-6 arsinio l-amino-iutphthslena- 
aoid. 4 aninio acid. 



NH. 

/\ 

UCH, 
A80(0H)ii 

d-amuio-tolyl-6 
arsinic aoid. 



NH 



AsO 



iO(OH)j 

l-chloro-2-ainino-phenyl- 
5 arsinic acid. 



P1CH3 
CH3U 

A80(OH)2 

l-4-dimethyl-2-aixiiD0- 
phenyl-5 aisinic acid. 

Benda and Kahn ^ showed that the reaction of arsenio acid with 
aromatic amines is a general one, if the para position to the 
amino group is free. They also noticed the formation of arsinic 

NH,— Rv j,0 
acids of the type y^^\ » *s well as those of the 



NHo— E 



/""N 



OH 



tjrpe NH2 — R — AsO(OH)2, but this had not been noticed by 
B6champ or by A. and B. Adler, who had just previously pre- 
pared 2-amino-tolyl-5 arsinic acid and l-amino-naphthalene-4: 
arsinic acid.^ 

By acetylation and subsequent oxidation of the former they 
obtained acetyl-anthranil-arsinic acid, which by hydrolysis yields 
anthranil-arsinic acid, which was then converted into salicyl- 
arsinic acid by the diazo reaction. 

NH . CO . CH3 
-> r^OOH 



NHj NH . C30 . CH 


^H, -> ACH3 


A80(OH)3 A80(OH)2 


NH, 


-* ACOOH -> 


A80(0H)j 

Anthianil-arsinto 
aoid. 



3 



AsO(OH). 



OH 
GOOH 




^80(0H), 

Salicyl-arsinic 
acid. 



f\*Pirfc-hydroxy-phenyl arsinic acid, H0<( )>A80(OH)2, is ob- 

' ' 1 Benda and Kahn, Ber,, 41 (1908), 1672. 

a A. and R. Adler, Ber., 41 (1908), 931. 



ARSENIC AND ANTIMONY COMPOUNDS 207 

tained from arsanilic acid by the diazo reaction,^ and it has also 
been obtained by the action of phenol on arsenic acid at 150'', and 
the homologues of this acid may be obtained in a simDar manner 
from ortho or meta cresol, or by the diazotization of the corre- 
sponding amino-acids.^ As obtained from phenol it is a syrup, 
and it can be purified by recrystallization of its sodium salt.^ 
Para-hydroxy-phenyl arsinic acid is not used therapeutically, but 
is the starting-point for the production of some very important 
derivatives. 

The arsinic acids of the type B^N ^ ^ — AsO(OH)2 and 
BHN ^ y — A80(OH)2 do not appear to have found any thera- 
peutic application. Para-dimethyl-amino-phenyl arsinic acid, 
(GH3)2N . CgH^ . AsO(OH)2, is obtained by the action of arsinic 
trichloride on dimethylaniline, whereby (OH3)2N . CgH^ . AsClj 
is formed, which is hydrolyzed, yielding the acid (CH3)2N . C^H^- 
— As(0H)2, which gives the arsinic acid by oxidation with 
hydrogen peroxide.* It is also formed by the action of dimethyl 
sulphate on an alkaline solution of arsanilic acid. 

An important derivative of arsanilic acid is phenylglycine- 
para arsinic acid, which is obtained by mixing solutions of 
sodium arsanilate with chloroacetic lacid in hot aqueous solu- 
tion — ^ 

H 
HO. I 

\As— / S— N— [H + CI]— CH2— COONa 
NaO^ II ^ — ^ 


HO . 

XAsO— / S— NH— CH2— COONa + HCl. 
NaO^ ^ — ^ 

This substance is of importance, owing to the fact that its re- 
duction product containing the arsenic in the trivalent condition 
is of great therapeutic value. This and other derivatives con- 
taining trivalent arsenic will be considered in the following 
section. 

^ Barrowcliff, Pyman, and Bemfry, J. C. 5., 93 (1908), 1898 ; Berthoim, 
Ber., 41 (1908), 1863. 

« D. R. P., 205,616. 3 E. P., 6322 (1916). 

*Michaeli8, Ber., 41 (1908), 1514 ; D. R. P., 200,605. 
'^J6td., 204,664. 



2o8 SYNTHETIC. DRUGS 

The benzene-sulphonyl derivative of atoxyl, 

.ONa 

CfiHg . SOa . NH< >As = O, 

is known as *' Hectine" and has been successfully used in the 
local treatment of syphilis.^ 

A compound of arsanilic acid with allyl-thiourea (c/. p. 239) 
has been prepared, and is said to have valuable therapeutic 
properties and low toxicity.^ 

The arsinic acids and their derivatives described in the pre- 
ceding pages are mostly prepared by the action of arsenic acid 
on a primary amine or a phenol, and this is the simplest method 
in those cases where it is applicable. A more general method of 
preparing arsinic acids has, however, been devised by Bart.^ It 
consists in diazotizing a primary amine, and treating the diazo 
solution with a metallic arsenite, and warming the product 
whereby nitrogen is evolved and the salt of the arsinic acid 
formed. 

E.NHa-^R.NaX 

R . NgX + As(0M)3 = R . NjAsO(OM)3 + MX 

R . NjjAsO(OM)3 -> R . AsO(OM)j, + Nj. 

By a suitable choice of the radicle represented by R, practically 
any aromatic arsinic acid can be prepared. 

Another widely applicable method of attaching arsenic to the 
aromatic nucleus is through the mercury compounds.^ 

Mercuric chloride readily reacts with many aromatic com- 
pounds, giving para-substituted mercury compounds : — 

R<CI> + HgClj = R<3HgCl + HCl. 
On treatment with arsenic trichloride, the mercury is replaced 
by arsenic : — 

R<CZ>HgCl + AsCl, = HgClj + R<^>A8C1,. 

The dichlorarsines so obtained are easily converted into arsinic 
acids by hydrolysis and oxidation. 

Triyalent Arsenic Compounds (Derivatives of Arseno- 
l>enzene). — ^The therapeutically valuable trivalent aromatic 

1 Lancet, 26 June, 1915. > D. B. P., 294,682. 

s Ibid., 250,264. « Boeder and Blasi, Ber., 47 (1914), 2748. 



ARSENIC AND ANTIMONY COMPOUNDS 20$ 

arsenic compounds are all of them obtained by reduction of 
the corresponding compounds containing pentavalent arsenic. 
Beducing agents convert arsanilic acid^ into para-amino- 

phenyl arsenious oxide, NHj — < ( ^ AsO, or into diaminodi- 

hydroxy-arsenobenzene, NHa< >As(OH)— As(OH)< >NHa, 
or into para-diamino-arseno benzene, 

NHa< )As = As< >NH2. 

The first is produced by weak reducing agents such as hydri- 
odic acid, or sulphurous acid, the second by sodium amalgam 
and methy alcohol, and the third by stronger reducing agents, 
such as sodium hydrosulphite, etc. 

Still stronger reducing agents, such as zinc and hydrochloric 

acid, reduce it to para-aminophenyl arsine, NH^ ^ ^ AsH^. 

As=As 
Arsenophenol, \ \ \ \ i& obtained by the reduction of 





ffl OH 

para-hydroxyphenyl arsinic acid with a solution of sodium hydro- 
sulphite, caustic soda, and magnesium chloride.^ The sodium 
derivative of this Substance is soluble in water, from solutions in 
which it is precipitated by alcohol. Phenylglycine arsinic acid 
when reduced in this way gives arseno-phenylglycine — 

As=As 

00 

HOOC . CH2— NH NH . CH2 . COOH 

a reddish-brown powder, soluble in aqueous sodium carbonate.' 
Very favourable results are said to have been obtained with 
this substance in the treatment of trypanosomiasis in rats, but 
it is not so well tolerated by larger animals, such as the horse 
or the donkey.^ Favourable results are also said to have 
attended its use in syphilis, and it is claimed that in aU cases 
it is free from the danger of harmful effects on the eyes. 

In recent years another derivative of arsenobenzene intro- 

1 M. L. B., English Patent, 17,619 of ld07 ; D. B. P., 206,057. 

« Ibid,, 206,456. > Ibid., 206/)57. 

^Breinl and Nierenstein, ZeUschr,/, IrnmuniUUsforach (1909), 169. 

14 



210 SYNTHETIC DRUGS 

duced by Ehrlich has been widely and successfully used in the 
treatment of syphilis. 
This preparation is dihydroxy-diamino-arsenobenzene — 

As=:j 





OH OH 

better known as "606" or Salvarsan, It is prepared from 
j)-hydroxy-phenyl arsinic acid, HO^^ )>A80 (0H)2, which on 
treatment with nitric and sulphuric acids yields a mono-nitro 
compound, the nitro group entering into the ortho position to 
the hydroxyl and meta to the arsinic group. This compound, 
on reduction with caustic soda, sodiupp hydrosulphite, and 
magnesium chloride, gives dihydroxy-diamino-arsenobenzene — ^ 

Na 

HO<~>AsO(OH), -► HO<_>AsO(OH)2 

As=As 
From two /\ 



Jn 



moleoules of * -gf) -oq 

nitro compound. 

An alternative method of preparing 3-nitro-4-hydroxyphenyl 
arsinic acid starts from ^dimethylaminophenyl arsinic acid, 
prepared as described on p. 207. This on nitration gives 3-nitro- 
4-dimethylaminophenyl arsinic acid, which on treatment with 
alkali gives 3-nitro-4-hydroxyphenyl arsinic acid.^ 

• 

AsOgHj AsOgHg AsOgHg 

(CH3)2 N(CH3)2 

In addition to the method already given, this can be reduced to 
dihydroxy-diamino-arsenobenzene by treating it with zinc and 
acetic acid at 25''-30^ and then with hydrochloric acid and 
sulphurous acid at 50°'6Qf', The addition of the sulphurous acid 
appears to prevent the reduction from going beyond the " arseno " 
stage.^ 

1 D. R. P., 224,953. «E. P., 22,621 (1914). 

» Ibid., 21,421(1914). 






ARSENIC AND ANTIMONY COMPOUNDS an 

Dihydroxy-diamino-arsenobenzene is obtainable as the hydro- 
chloride under the trade names of Salvarsan, Kharsivan, and 
Arsenobenzoly but before use it is generally ^ transformed into the 
sodium salt by adding the correct amount of caustic soda solution 
to its aqueous solution. Great care has to be taken in making up 
these solutions, which do not keep well, so that they have to be 
prepared immediately before use. They are administered either 
by intravenous or intramuscular injection. 

Splendid results have been obtained with this compound, 
especially when used in conjunction with mercury, though 
some of the more extravagant claims, as for example, that 
syphilis could be cured by a single injection, have not been 
substantiated. 

Although its toxicity is low, it is by no means negligible, 
and fatal results have sometimes attended its use, but in the 
majority of cases these can be attributed to faulty technique or 
to its use in cases where the condition of the patient was already 
very bad. Its action on spirochaetes in vitro is very weak, 
and it was therefore presumed that it underwent some change 
in the organism with the formation of more active products. 
According to a recent investigation,^ these changes are very 
complex, a large number of different compounds being formed. 

To overcome the drawbacks due to the laborious technique 
of administering Salvarsan, a derivative soluble in water was 
soon afterwards introduced. This substance is known as Neo- 
salvarsan, Neokharsivan, Novarsenobenzol, etc., and has the 
structure represented by the formula : — 

As=As 
HgNisJ UnH— CH,— SOjjNa 

It is prepared ' by adding an aqueous solution of formaldehyde 
sulphoxylate to an aqueous solution of Salvarsan. A precipitate 
is formed which redissolves in sodium carbonate solution to 
form a dear yellow solution of Neosalvarsan. 

^ The hydrochloride itself, in aqueous solutions or oily suspensions, has 
also been used for injection. 

a Sieburg, ZeiL physioh Cham., 97 (1916), 68-108. 
»D.R. P., 246,766. 

14* 



212 



, SYNTHE TIC DR UGS 



Not only does NeosaJvarsan possess the advantage of ready 
solubility in water and in saline solutions, giving neutral solu- 
tions, but it is also said to be better tolerated by patients than is 
Salvarsan itself. It is administered by intravenous or intra- 
muscular injection, and its therapeutic properties are similar to 
those of Salvarsan. 

Another derivative of Salvarsan which has recently attracted 
a good deal of favourable attention is Galyl, a substance having 
the composition shown by the formula : — 

As 








NH O NK 

H \||/ OH 
P 

I 
OH 

It is prepared as follows : 8-nitro-4-hydroxyphenyl arsinic acid 
is eleotrolytically reduced to 3-amino-4-hydroxyphenyl arsinic 
add.^ This is then treated with phosphorus oxychloride in 
presence of caustic soda, solution, and the product reduced with 
solium hydrosulphite.^ 

AsOgHg 



AsOjH 




2 




NOg /yNHs 

/2 Mols + 1 POClg 



AsO^ 

NH NhU 
H \/ OH 
PO(OH) 




AsOj^i 



AB: 



:AS 



Q 



/\ 



NH NH 
OH \/ 

PO(OH) 



Yh 



It is used in the form of its sodium salt which is readily soluble 
in water, yielding solutions suitable for intravenous injection. 
Its solution in a dilute solution of glucose is also used for intra- 
muscular injection. 

Considerable attention has been paid recently to the metallic 
compounds of Salvarsan. These are of the "additive" type, 

1 E. P., 8087 (1915). a Jhid,, 9234 (1915). 



ARSENIC AND ANTIMONY COMPOUNDS 2t3 

and are formed by virtue of the residual affinity of the " arseno," 
-^As= As — group.^ A compound of one molecule of Salvarsan 
with one molecule of cuprio chloride is said to be remarkably 
effective against sleeping sickness. The preparation is described 
of copper and of silver compounds, by mixing a solution of 
Salvarsan with a copper or a silver salt, and precipitating the 
mixture with a solution of caustic soda.^ 

" Sodium Salvarsan " is prepared by precipitating a solution 
of Salvarsan in caustic soda with alcohol, in the presence of a 
substance capable of stabilizing the product.^ It is said to be 
useful in the treatment of syphilis.^ 

Various other metallic derivatives and their methods of 
preparation have since been described.^ One of these is known 
as '^Imargolj' and is a compound of Salvarsan with silver 
bromide and antimony. It appears to have the composition^ 
(Ci2Hi202N2Asjj)2, AgBr, SbO(H2S04)2, and is said to be stable 
and to be less toxic and more effective therapeutically than the 
parent substance.*^ 

In addition to the derivatives of Salvarsan, various more 
complex derivatives of arsenobenzerie have been prepared and in- 
vestigated. For example, 3-4-5-3'-4'-5'-hexamino-ars6nobenzene 
is said to be a powerful spirillodde.® 

Besorcinol readily reacts with arsenic acid giving 2-4-di- 
hydroxyphenyl arsinic acid, from which a series of derivatives of 
arsenobenzene have been obtained by reduction.^ 

From a-aminoanthraquinone, the corresponding arsinic acid 
has been prepared by Bart's reaction (p. 208). This on reduc- 
tion with sodium hydrosulphite gives l-l'-arsenoanthranol : — 
CH(OH) As A s CH(OH) 

/\/ \/\, /\/ : \/\ 

II II II II 

CH(OH) CH(OH) 

which is readily oxidized by air to anthraquinone-1-arsenoxide : — 

1 Ehrlich and Karrer, Ber., 48 (1916), 1634. 

« E. P.^ 1247 (1914). 8 Ibid., 15,931 (1912), 24,152 (1914). 

* MUnchenermed. W. (1916), 177. 

»Danysz, E. P., 104,496; 104,497 (1916). 

"Danysz, C. U., 169 (1914), 452. 

^ C. i?., 161 (1916), 686, 162 (1916), 440. 

« D. B. P., 286,854, 286,865. » Bauer, B«r., 48 (1916), 609. 



ai4 SYNTHETIC DRUGS 

CO AsO 

I I I 

CO 

These compounds are toxic, and they are easily decomposed 
into anthraquinone and arsenic aoid.^ 

A very large number of other derivatives of phenylarsinic 
acid and of arsenobenzene have been described, the above- 
mentioned having been given as typical examples. 

In addition to the symmetrical derivatives of arsenobenzene, 
R — As = As — R, already mentioned, mixed or unsymmetrical 
derivatives of the type R — ^As — As — R' can be obtained by the 
reduction of an equimolecular mixture of arsinic acids, RAsOgHj 
and R'AsOgHg.^ Another method of obtaining unsymmetrical 
arsenobenzenes is as follows : The arsinic acid is first reduced 
to the corresponding arsine by means of metal and mineral acid,^ 

R . AsOjHa -> R . AsH^, 

and this can then be condensed with aryl arsenoxides or halides. 

R . AsHj + OAsR' = R . As = As . R' + H2O.* 

This method is also applicable to the production of mixed arseno- 
stibino, and arseno-bismutho compounds ^ (c/. p. 215) : — 

R .AsHa + R'SbCla = R. As = Sb.R' + 2HC1. 

As can be seen from the preparation of Salvarsan, the use 
of sodium hydrosulphite is not applicable to the formation of 
arseno compounds containing a nitro group as this is also re- 
duced by the hydrosulphite. It has been found, however, that 
hypophosphorus acid is a specific agent for reducing the arsinic 
acid group to the arseno group, and by this means arsinic acids 
containing a nitro group or an azo group can be reduced to the 
corresponding arseno compounds.^ 

Orsranic Antimony Compounds. — The trypanocidal action 
of antimony, compared with that of arsenic, has been discussed 
in the first section of this chapter. Unfortunately, the aromatic 
antimony compounds compare unfavourably with those of 

^ Benda, Journ.prakt. Chem., 95 (1917), 74. 

a D. R. P.. 261,104, 270,254. » JMd., 251.761. 

* Ibid., 251,611. 

^Ibid., 264,187, 269,699, 269,748, 269,744, 269,746. 

• Karrer, Ber., 47 (1914), 2275 ; D. R. P., 271,271. 



ARSENIC AND ANTIMONY COMPOUNDS 215 

arsenic with regard both to ease of preparation and stability. 
Por example, j?-aminophenyl-stibinio acid, the antimony analogue 
of arsanilic acid, cannot be obtained by the interaction of anti- 
mony pentoxide and aniline, and the statement ^ that it has been 
obtained from aniline and antimony trichloride by a method 
analogous to Michaelis's synthesis of ^-dimethylaminophenyl 
arsinic acid (p. 207) is quite incorrect. 

Aryl-stibinic acids can, however, be obtained by the action of 
sodium antimonite on diazo solutions ^ in a way somewhat 
analogous to Bart's reaction (p. 208), and jp-aminophenylstibinic 
acid has been prepared by this method, but the preparation is 
difficult and the yields are low. The compound moreover is 
amorphous and difficult to purify. Aryl-stibinic acids can also 
be obtained by the action of alkali ^ on compounds obtained from 
antimony trichloride and diazo compounds.* 

Aryl-stibinic acids can be nitrated in the usual way,* and 
|}-chlorophenyl-stibinic acid on nitration gives 3-nitro-4-chloro- 
phenyl-stibinic acid, which, on boiling with alkali, gives 3-nitro- 
4-hydroxyphenyl-stibinic acid. This, on reduction with sodium 
hydrosulphite, gives 3-3'-diamino-4-4:'-dihydroxy-stibinobenzene, 
the antimony analogue of Salvarsan.^ 

A large number of other aromatic antimony compounds, and 
mixed arseno-stibino compounds have been prepared^ (c/. p. 214:). 

None of the compounds which have been tried up to the 
present fulfil all the conditions necessary for a really efficient 
trypanocide. These conditions may be summed up as follows : — ® 

(1) The compound must be non-irritant, and capable of re- 
maining in perfect solution at the temperature and alkaJinity of 
the tissues. 

(2) It must act quickly on the trypanosomes before they can 
acquire a tolerance to the drug. 

(3) When the trypanosomes have been expelled from the 
blood by a single full therapeutic dose, there must be no recur- 
rence in the majority of cases within some fixed time, which will 

^ Breinl and Nierenstein, Annals of Tropical Medicine^ 2 (1909). 

a D. R. P., 254,421. ' Ibid,, 261,826. 

* P. May, J. C. 5.. 101 (1912). 1037. * Ibid., 1083. 

«D. R. P., 268,461. 

7 Ifeid., 259,876, 269,205,267,083, 254,187,269,699, 269,743,269,744. 

^ Thomson and Gushny, Proc. Boy. Soc., 82 B (1910), 249. 



216 SYNTHETIC DRUGS 

depend to some extent on the particulftr host experimented with, 
and on the strain of parasites used. 

Although the arsenic compounds which have heen described 
do not fulfil the second and third of these conditions, yet the 
majority of them fulfil the first of these quite admirably, but in 
the case of antimony difficulty has been experienced in obtaining 
derivatives to fulfil even this condition. 

Of the various compounds which have been tried therapeuti- 
cally, those of a similar nature to ordinary tartar emetic (potassium 
antimonyl-tartrate) are amongst those giving the best results. 
Thomson and Cushny* have experimented with many com- 
pounds of this type derived from various hydroxy acids, and the 
best results were obtained with compounds prepared from tar- 
taric and malic acids : — 

HO— CH— COOH HO— CH— COOH 

HO— CH— COOH CHa- COOH 

Tartorio Aoid. Malio Acid. 

The sodium and potassium antimonyl-tartrates seemed to be 
very nearly equal in their efficiency, but the ethyl ester of anti- 
monyl-tartaric acid appeared to have some advantage over these 
alkali salts. Potassium ammonium antimonyl-tartrate is known 
as AntUuetin, 

Good results are also claimed for certain antimony derivatives 
of thioglycoUic acid.* 

The injection of finely divided metallic antimony has also 
been advocated as the most satisfactory treatment of trypano- 
somiasis.' 

1 Thomson and Ouahny, Proc, Roy. Soe., g2 B (1910), 249. 

" Bowntiee and Able, Ths Journal of Pharmacology (Baltimore), 2, (1910), 

'Plimmer and Pry, Proc. Roy. Soc, 81 B (1909), 884. PUmmer, Fry, 
and Ranken, Proc. Roy. See., 83 B (1910), 140. 



CHAPTBE XV. 

PUBINE DERIVATIVES (DIURETICS) AND OTHER URIC ACID 

ELIMINANTS. 

Caffeine, the best-known drug of the purine group, is used as 
a cardiac tonic and cerebral excitant, but in addition it has a 
diuretic action, as also have other members of the purine group. 
Cafifeine sodium cinnamate is known as Hetol, 

CH3— N— CO HN— CO 

I I yCH3 I I /CH, 

CO C— N< CO C— N<; 

I II >H I II \CH 

CH3— N— C— N^ CH3— N— C— N^ 
GafEeine. Theobromine. 

CHa— N— CO H CH3— N— CO ^_ ' 



A 



O C— N CO C— N 



\CH 



\CH 



CH3— N— C— N H— N— C— N 

Theophylline. Paraxanthine. 

A lthough the action of theobromine on the nervous sys tem is 
far weaker than that o^ ^rft^^^^*^, ^^° ^i^y^*^'^ n.r>f.irkn ia ^f^ gf.rnnpr 
Both substances sufifer from the disadvantage of spari ng solu- 
bilit y and small power of resorptio n] To overcome the draw- \ 
back of alight solubility, double salts of the sodium derivatives I 
of , caffeine and theobromine, with sodium salicylate, benzoate, * 
and acetate, have been prepared. « Compounds of sodium theo- 
bromine with sodium salicylate and acetate are known as 
Diuretin and Agurin respectively. The acyl-amino derivatives v 
of caffeine are said to have a strong diuretic action without the 1 
by-effects of caffeine. Monoacetyl-amino-caffeine, diacctyl- 
amino-caffeine, etc., have been prepared.^ 

1 D. R. P.. 139,960. 
217 



2i8 SYNTHETIC DRUGS 

Aooording to the investigations of Ach,^ the dimethyl-| 
xanthines have a stronger diuretic action than trimethyl- 
xanthine (caffeine). Of these, theobromine (3-7 dimethyl) 
has the weakest, and <:Wip>iyllin<^ ^.3 dimethy l) the strongest 
action, but that of paraxanthine (1-7 dimethyl) is the most 
persistent. TheophyllinB, which differs from caffeine in having 
less action on the heart, has been introduced into therapeutics 
tmder the name of Theocine, in the form of its compound with 
sodium acetate. Its practical application is due to a synthetic 
process, as the natural alkaloid is far too expensive. 

Theophylline has been synthesized by Fischer and by 
Traube,' the technical preparation being based on the latter 
method.' 

The synthesis of theophylline was carried out by Traube 
according to the following method. Dimethyl urea was first 
condensed with cyanacetic acid by means of POCl,, and the 
resulting compound (II.) converted into the cyclic base (III.) 

CH,— N(H HO)— CO CH,— N CO 

I I POCI3 I I 

CO + CH2 > CO CH2 



CH,— NH CN CH3— NH 



II. 



CH3— N— CO 



CN 

1 



CO CH^ ' 

-U 

III. 



CH,— N— C=NH 



by the action of alkali. This base, when treated with sodium . 
nitrite and aoetio acid, yields the isonitroso compound (TV.) ' 

CH,— N— CO CH,— N— CO 

CO C=N— OH ► CO C— NH, 

I J, I II ' 

CH,— N— C=NH CH,— N— C— NHj I 

IV. V. ^ 

> Aoh, A. «. P. P., 44 (1900), 319. ' W. Tmubs, Ber., 33 (1900), a063. 

* D. B. P., 138,444. 



URIC ACID ELIMINANTS 



2ig 



CHj— N— CO 

-* coc- 



OH,— N— CO 



"» 



NH— CHO 



CH,— N— C— NH 



2 



OH, 



VI. 



CO C— NH 

>CH 

N— C— N 
VII. 



which is reduoed to the corresponding amine (V.) by means of 
ammoniam stdphide. This amine is then converted, by formic 
acid, into its formyl derivative (VI.), which loses HjO and 
yields theophylline (VII.) when heated with alkali. 

8-Amino-theophyIline is obtained by the action ammonia on 

CHg— N— CO 
~* COC— ] 



CHg— N— CO 



I I 



CH,— N— C 



CO C— NH 

\(i-Cl 

N 



-NH 
\C— NH 



OH,— N— C— N 



^ 



2 



'3 



8-chloro-theophylline,^ and has strong diuretic action. 8-Amino- 
paraxanthine and its alkyl derivatives have been obtained in 
a similar manner.^ 

3-Monomethyl-zanthine has an appreciable diuretic action, 
but in 7-moriomethyl-xanthine it is vanishingly small. The 
diuretic action of xanthine itself is extremely small, and that of 
iso-caffeine (1-7-9 trimethyl-xanthine) is also very weak. 

Uric Acid Solvents, etc. — In addition to the diuretics, the 
variqus compounds that have been advocated as remedies for 
gout may be divided into two classes — ^those which are designed] 
to diminish the formation of uric acid in the body, and those | 
which are intended to act as solvents for the uric acid after it 
has been formed. Of the latter class it may be said that many 
substances have been obtained, such as jaiperazine and urotro-. 
pine, which are capable of dissolving uric acid in vitrOf but are! 
probably quite incapable of dissolving it in the highest possible 
concentrations that can be present in the body. Naturally 
many compounds have been prepared which are intended to 
combine both functions. 

For example, quinic acid, CgH7(OH)4 . COOH, which exists 



1 D. B. P., 156,900. 



a I6td., 156,901. 



220 SYNTHETIC DRUGS 

in cinchona bark and coffee beans, is said to diminish the forma- 
iion of uric acid,^ and its lithium and piperazine salts have 
been introduced under the names of Urosin and Sidonal respec- 
tively. In these cases the lithium or piperazine is intended to 
act as a uric acid solvent. 

It has also been noticed that the presence of organic acids in. 
the organism generally decreases the amount of uric acid formed,! 
and that this effect is greater in proportion to the number of I 
carbon atoms present in the acid. For this reason the use of 
diphenyl tartrate has been suggested, ( — CH(OH) — COOCgH5)2, 
and salicylic acid has also been used, especially in the form 
of a condensation product of saligenin and tannic acid. A 
salicylate, of urea has been recommended under the name of 
Ursal. Other compounds used for this purpose are hippuric 
acid, methylene-hippuric acid— 

.CHg— CO 
C.H.-<=0-H<^_J 

and its meta-nitro compound.^ 

Drugs of the second class, namely those the function of 
which is to prevent the deposition of uric acid rather than to 
prevent its /orwaiion, are more numerous. The alkaline car- 
bonates have been widely used for this purpose, and especially 
lithium carbonate, as it has been iound that the lithium salt 
is by far the most soluble of all the inorganic salts of uric acid. 
The alkaline tartrates, citrates, etc., are also used as well as 
the carbonates. The bad effects of lithium on the nervous 
system have led to the introduction of various organic bases 
which form even more soluble salts with uric acid. 

The employment of lithium and these bases as uric acid 
solvents is fallacious, because there is always sufficient sodium 
present in the body to form the sparingly soluble sodium urate, 
and a double decomposition between salts takes place with the 
formation of the least soluble. If we designate sodium urate 
for the sake of simplicity as NalJ, then an equation such as 
LiU + NaCl -^ NaU + LiCl, will run from left to right under 
the conditions present in the organism. Nevertheless, some 

J Weiss, Betl, klin. W., U (1899). ^ D. R. P., 148,669. 



acid. 



URIC ACID EUMINANTS 221 

considerable benefit is often derived from these remedies, al- 
though it may not be due to their solvent action on the uric 



Of the various organic bases that have been used as substi- 
tutes for lithium, piperazine is the most important. It was 
obtained by Hofmann by the action of ammonia on ethylene 
dichloride or dibromide.^ 

,H + Br— CH2— CHo— Br Hv 
HN<: + >N— H 

\H + Br— CH2— CH2— Br H^ 

= HN< >NH + 4HBr. 

It is most readily purified by treating the reaction mixture with 
nitrous acid, whereby nitroso-piperazine — 

ON— N< >N— NO. 

\CH2— CH^/ ^ 

is obtained, from which piperazine can be regenerated by the 
action of hydrochloric acid or reducing agents.^ 

Many different modifications of this synthesis have been 
devised,^ but only one of them calls for mention. By the action 
of aniline on ethylene dibromide, diethylenediphenyldiamine is 
obtained,^ which yields a nitroso compound on treatment with 
nitrous acid. It has been 'shown '^ that this on treatment with 
alkalies yields piperazine and nitroso-phenol. 

Aniline with ethylene dibromide gives — 

^CHa — CHc 



^CHo— CH / 



just as ammonia gives piperazine. 
This with nitrous acid yields — 

1 Hofmann, Proc, Ray. Soc., 10 (1860), 231 ; B&r,, 23 (1890), 3297. 

* D. R, P. 69 222. 

3IWd., 00,547, .63,618,66.461, 66,347, 70,065, 71,576, 88,524, 70,056, 
73,126, 67,811, 73,354, 74,628, 98,031, 100,232. See Friedlander, Fort8chr., 
III. 948, IV. 1201. 

^Hofmann, Proc. Boy, 80c., 9 (1858), 277. 

^Bischler, Ber., 24 (1891), 717 ; and D. R. P., 60,547, etc. 



2M SYNTHETIC DRUGS 



.GM2 — CH2> 



ON— CgH^— N<f ^N— CaH^— NO 

\OHj— CH/ 

|NaOH 

CH«— CH 
ON— C«H^— OH + HN^ * \nH + HO— CeH^— NO 

^CHa— CHa^ 

Piperazine is also known under the name of Dispermin, and 
its salt with quinic acid (p. 220) is used under the names of 
Urol and Sidonal. 1 

GH2 — CH— CHg 

The tartrate of dimethyl-piperazine, NH<^ \NH , 

GH2 — CH — CHg 

is known as Lysetol, and has the advantage of being non-poison- 
ous and non-hygroscopic. Dihydroxy-piperazine has also been 
investigated, and it resembles piperazine in its properties of a 
uric acid solvent. It is obtained by polymerizing aminoacetal- 
dehyde with cold hydrobromic acid.^ 

NH 

/ \ 
BJO CH— OH 

2NH2.CH2.CHO = I I 

HO— HO CH2 



NH 



CH2— N. 



Anethylene-ethenyl-diamine, I yC — CH3, has been pre- 

CHa— NH 

pared ^ by heating ethylene diamine hydrochloride with sodium 
acetate and introduced under the name of Lysidin, It is said 
to be eight times as strong as piperazine in its solvent action 
on uric acid in vitro.^ Similar propenyl and butenyl deriva- 
tives have been prepared.^ 

Urotropin (hexamethylene-tetramine), cf. Chapter XI., has 
been recommended as a uric acid solvent, its salts with quinic 

^ E. Fischer, Ber., 27 (1894), 169. 

"Ladenburg, B«r., 27 (1894), 2962; D. B. P., 78.020. 

^Deut. med. T7., 1 (1894). 

« Klingenstein, Ber., 28 (1896), 1173, 3068. 



URIC ACID BLIMINANTS 223 

acid being known as Quinotr<ypin, and its salicyl derivatives 
as Saliformin. Helmitol, or New-urotropin, is the anhydro- 
methylene-citrate of hexamethylene-tetramine. The aoid, 

^Ov.,^ .CH2— COOEt 
CHj^ ^yC!\ ,ns obtained by heating citric 

^O— CO^ ^CHj— COOH 

acid with paraformaldehyde, or in better yield by the action of 
chlor-methyl alcohol, CI . CHg — OH, on citric acid at 130°- 
140" C.i 

The sodium salt of the acid has also been used by itself as a 
uric acid solvent, under the name of Citarin. 

Ap^riling t.n TnnniAliffA ft,|^^ Boseuheim. the solubi lity of 
uric acid in blood serum is raised by the presence of piperidine, 
and they suggested the use of piperidine tartrate.^ 

A substance of unknown composition which is used a good 
deal as a uric acid solvent is thyminic acid, a complex substance 
prepared by a lengthy process from the thymus gland.^ It is 
also known by the trade name of Solurol, On boiling with 
aqueous sulphuric acid, it breaks down into Thymin, 

/NH— CO. 
C0\ >C-CH3, 

\NH~CH^ 

which shows that it is chemically related to piperazine, lysidine, 
etc. 
Various other cyclic bases of this type, such as, 

.CH(CHo)— N;-CH, 
CHo— NC >CH . CH„ 

\CH(CH3)— N^CHj 

also have a strong solvent action on uric acid.^ 

Ceg t&in quin oline derivatives have been found useful in the 
treatment of gout, sciatica, etc., as they have analgesic pro- 
perties in addition to being unc acid eliminants and urinary 
antiseptics. The simplest of these is Atophan, or 2-phenyl- 
quinoline-4 carboxylic acid, 

1 D. R. P., 129,266, 150,949. « Lancet (18)39), 189. 

»D. R. P., 104,908. 

^ * Unpublished observations of the author. 



334 SYNTHETIC DRUGS 

COOH 



\/\,/-C«H,. 



Ir 



Its ethyl ester is known as Acitrin, and the methyl derivative of 
this, 

COOCgHfi 



N 



— CgHj 



is known as Novatophan, 



CHAPTER XVI. 

PURGATIVES AND OTHER SUBSTANCES ACTING ON THE 

GASTRO-INTESTINAL TRACT. 

Anthraquinone Derivatives. — Many aperient drugs, suck as 
casoara, rheum (rhubarb), senna, and aloe, contain hydroxyl 
derivatives of methyl-anthraquinone. The position of the 
methyl group in these substances is not quite certain, but it is 
[probable that most of them are derivatives of a-methyl-anthra- 
quinone, 

These substances are very valuable as purgatives, owing to 
the fact that they have but little effect on the stomach and do 
not cause inflammation of the intestine. On the other hand, 
some of the drug is absorbed from the intestine into the system, 
and is liable to have an undesirable action on the kidneys. 
This effect is usually very slight, however. 

Chrys ophanic a cid, dihydroxy-methyl-anthraquinone — ^ 








\co/' 



is one of the milder of the natural purgatives of this group, and 
is present in rhubarb and many other purgative drugs, usually, 
as a glucoside, chrysoghan. Thft n^^mber and position o f the 
hydroxyl groups has a powerful influen ce on the physiolog ical 
action of i^*j;ub^nce. _iror example, emodin, trihydroxy- 
methyl-antE'iuquinone, G^^'EL^qO^, probably having the constitu- 
tion — ^ 

. 1 Jowett and Potter, /. C. S., 85 (1903), 1327. 

^ s Hesse, Armalen, 309 (1899), 32. 

225 15 



326 



SYNTHETIC iDR UGS 



CH,^CO\ OK CH3^cO\ OH 

HOT I 



^°^co/Qh 



u 



\co/ 




has a considerably more powerful action than chrysophanic 
acid. This substance is obtained together with rhamnose by 
the decomposition of the pentoside/ran^i^Zin, obtained from the 
bark of Bhamnus frangula, and from other similar sources. 

C21H20O9 + 2H,0 = (CH, . G.'ELfi, + H,0) + C^^K^fi^- 

Rhamnose. Emodin. 

The active principles present in different varieties of aloes are 
known as aloi'n, GiyH^gOy + iH^O, and barbaloi'n, G^oH^gOj. 
The structure of these compounds is not known with certainty, 
but they are undoubtedly derivatives of polyhydroxy-anthra- 
quinones. 

The purgative action of the synthetic hydroxy-anthraquinones 
has been investigated by Yieth, and his results ind ^fifttft that th e 

but that the presence of the methyl group seems to have little 
influence on'tne physiological action. He found that the most 
active was dnlRirapurpurinj i-2-7 trihydroxy-anthraquinone — 




Snbstaiice. 


Strength of Action. 


Anthrapnrpurin, 1-2-7 trihydroxy-anthraquinone . 
Flavopnrpurin, 1-2-6 „ „ 
Anthngallol, 1-2-3 „ „ 
Porpuroxanthin, 1-8 dihydroxy- „ 
Alizarine-Bordeaux, 1-2-8-4 tetrahydroxy- „ 
Pnrpurin, 1-2-4 trihydroxy- „ 


1 



A number of compounds, such as a lfza^y in (1-2 dihydroxy- 
anthraquinone), rufigallic acid (hexa-hydroxyanthraquinone), ^ 
etc., are i nactiv e. Some oLthe actiyja._c ompounds c ontain a I 
methyl group, and_ others do not. « 

An important factor in determining the purgative actioais the 



PURGATIVES AND OTHER SUBSTANCES 227 

length oft ime that the anbatance remains in the intestin e, for 
when it is abso rbed it can no longer exert a purgative act ion.^ 
The superiority of the gluoosides and i^cetyl derivatives over 
the parent substances, and of the natural drugs over the syn- 
thetic, is due to the slower absorption of the former. Chryso- 
phanic acid when quite pure is no longer a purgative, owing to 
its rapid absorption.^ Bapid absorption also increases the risk 
of undesirable effects on the kidneys, and therefore it is to be 
avoided on this account also. For these reasons, synthetic 
substances such as anthrapurpurin are inferior to the natural 
compounds, but synthetic substances of a more complex nature 
which are slowly absorbed have also been obtained. 

AnthrapurpurL diacetate has been tried aa a mUd laxative 
under the names Purgatin and Purgatol, but it is a kidney irri- 
tant. The acetyl derivatives of the tetra-alkyl ethers of rufigallic 
acid have been recommended as purgatives.^ Exodin is said to 
be the tetramethyl ether of the diacetyl compound, but accord- 
ing to Zernik ^ it is a mixture of several substances, of which 
the hexamethyl ether is the one to which the purgative action is 
due, the diacetyl tetramethyl ether being inert. Exodin is a 
mild purgative. 

Many derivatives of aloin have been prepared which are in- 
tended to be free from the bitter taste of the parent substance 
whilst retaining its purgative action ; these, being only slowly 
decomposed in the intestine, should be more active. A deriva- 
tive of aloi'n and formaldehyde has been prepared in which the 
methylene group enters into two hydroxyl groups — ** 

Cl7HiA{0H)a + OCHj - C^jR,fi,<^ ^CH^ + H^O. 

Its action resembles that of aloi'n itself. H. Meyer has. pre- 
pared tribromcUo'in, G^jH^gOyBrj, which has a milder action than 
aloi'n, and triacetyl aloin, Gi7Hi507(GO . CB.^)^, which is as 
powerfid as the parent substance in its action, and has the 
advantage of being tasteless and keeping well. An oxidation 

^ This statement of coarse only applies to substances such as these, 
which act locally. It does not apply to apomorphine, etc. 

> Dixon, " Manual of Pharmacology." < D. B. P., 151,724. 

* Zamik, Apoth, Zeitg., 19i fi98. ^ D. B. P., 86,449. 

15* 



3^8 SYNTHETIC DRUGS 

product obtained by the action of persulphate on aloi'n ^ has a 
weak purgative action, and is free from harmful by-effects. 

A glucoside having a purgative action has been obtained from 
cascara sagrada, and named Peristaltin, 

HO— CgH^ O 
PhenolphthaUiny y^\ y^^» although not an 

HO-CeH, • C,H, 

anthraquinone derivative, has a purgative action without harm- 
ful effects on the kidneys, and has attained wide use as a laxative 
under the names Purgen and Laxin. It sometimes causes grip- 
ing, and to overcome this drawback its acetyl-valeryl derivative 
has been introduced, under the name of Aperitol. 

Drastic Pursratives. — Very little is known of the chemical 
nature of these substances, whi ch act by reason of their gener ally 
ir ritant propertie s. In large doses they give rise to bad effects, 
bul in thfiir STiftnifia Joses thev act more promptlv than the 
anthraquinone derivatiyes, though they are apt to cause nausea 
and vomiting. 

Crot'on oil contains a large number of substances, but its in- 
tense purgative action is probably due to a resin, G^sH^gO^.^ 
The action of jalap has also been attributed to a resin, which is, 
however, a mixture of several substances.^ 

The active principle of podophyllin is podophyUtoxirif 
G^gHj^OQ, a neutral substance, which when heated with alkali 
forms podophyllinic acid, G^gH^gO^. By loss of water this acid 
forms picropodophyllin, G^^^^fi^, an isomeride of podophyllin, 
and on further treatment with alkali yields acetic acid and 

OH 

orcine, GH ^ ^ ' PicropodophyUin is probably the lactone 
^)H 

of podophyllinic CLcid, these substances being regarded as de- 
rivatives of y-pyrone.* 

1 D. R. P., 134,987. 

> Danstan and Boole, Proe, Roy, 8oc., 58 (1895), 238. 
' Powar and Rogerson, Pharmaceutical Journal, 29 (1909), 7 ; Joum, of 
American Chem. fifoc., 32 (1910), 80. 

« Danstan and Heniy, J. C, S., 73 (1898), 209. 



PURGATIVES AND OTHER SUBSTANCES 



229 



OCH 





CH CH— COOH 



OCH, Ar, (!,H_. 



\/ 
CO 

Podophyllinio acid. 


CH CH 



OH 



OCH 
CH /~\ 



OCH 



-CO 
I 



3 CHjCH— O 

\/ 
CO 

Picropodophyllin. 

These two substances are without definite purgative action.^ 

Other Substances acting: on the Oastro-Intestinal 
Tract. — Ph Auyl-dihydrnqiiinazoUne was acoidentally found to 

possess a bitter taste, .<^VA *" p'-^'^""" g^" anrly foaling nfhnngnr 

N 
CH 
N— CH. 



e-" 



CH, 

and henoe it has been introduced as an aperitive,^ under the 
n ame of Ore xin. Other substances of this type have also been 
investigated, but none of them are so satisfactory as this one. 
Dihydroquinazolines of the type — 

Quinazoline is — 



N 

CH 

N— E 
CH, 



N 
CH 



N 
CH 



> Mackenzie and Dixon, Edinburgh Med. Joum. (1898), 134. 
' Aperitive denotes a substance used to stimulate the appetite. 



T - 

1 



330 



SYNTHETIC DRUGS 



are formed by the reduotion of orthonitrobenzylform-anilides, 
-toloides, eto. — * 

/\/ o 

CH 
I 

. CH, 



/NO, 
0,H,/ /CHO 

OrthonitiobAnzyUonn-tuiiUde. 



N 

OH 
I 



+ H,0 



N-0,Hj 

OH, 

Orezin is also prepared by the action of formaoilide on ortho- 
aminobenzyl alcohol — * 

,NH, H . 00 



a 



\CH,— OH 



/N-0,H, 



cc" 



^OH 



+ 2H,0 




N-0,H, 



2^ 



CH3 



Orezin is used in the form of the hydrochloride, owing to the 
bad taste of the free base. The tannate is insoluble in water 
(c/. quinine), and therefore is quite tasteless. It is soluble in 
hydrochloric acid, and therefore dissolves in the gastric contents, 
and can exert the required action. It is now largely used in- 
stead of the hydrochloride. 

Coto-bark has a specific efifect on the walls of the intestine, 
dilating them and helping resorption, which renders it of use 
in diarrhcBa. Its active constituent is coto'in, Gi^^i2^^y a de- 
rivative of benzophenone and phloroglucinol having the 
formula — 

CH3O . C,H,(OH),-CO-CeH,. 

1 D. R. P., 51.712. «I6kJ., 113.163. 



PURGATIVES AND OTHER SUBSTANCES 231 

This subsl»ance has a sharp taste, and in order to overcome 
this disadvantage, various derivatives have been prepared, 
one of which, known as Fortotn, is a methylene-dicotoi'n, 
CH2(0i4HiiO4)2, formed by the action of formaldehyde on 
cotoi'n.^ It is free from the sharp taste of cotoi'n, and is 
said to have a stronger action, having especially an enhanced 
bactericidal effect. 

Condensation products of cotoin with phenols have been 
prepared,^ which have the antiseptic action of the phenols 
combined with the beneficial effects of coto'in on the intestines. 

ID. R. P., 104,362. ^Ibid., 104,963. 



CHAPTER XVII. 

VARIOUS OTHER COMPOUNDS OP INTEREST. 

Glucosides. — Several gluoosides which owe their physiologioal 
activity to their hydrolytic cleavage products have been mentioned 
in other parts of this volume. It will suffice to recall such 
compounds as salicin and chrysophan. Besides these, there 
are numerous glucosides which have a powerful and character- 
istic physiological action of their own. The most important of 
these are the active principles of digitalis and strophanthus, 
drugs having a powerful action in increasing the strength and 
diminishing the frequency of the heart-beat. Digitalis contains 
several active glucosides, but unfortunately very little is known 
of their chemical constitution beyond the fact that most of them 
are derivatives of substances allied to cholesterin. The most 
important are digitalin and digitoxin ; the latter, on warming 
with caustic soda, yields the physiologically inert digitoxic acid. 
The active constituent of strophanthus is a glucoside, strophan- 
thine G^f^ofiigt which on hydrolysis yields strophanthidin, 
C27H3SO7, and a carbohydrate, Gi3n240io* Strophanthidin con- 
tains two lactone groupings, a benzene nucleus, an unsaturated 
linkage, — CH=CH — , and probably three hydroxyl groups. 
The carbohydrate, O13H24O10, is the methyl ether of a biose. 

Various other important glucosides have been mentioned in 
the previous chapter. 

Many physiologically active compounds are ''glucosides" 
derived from pentoses instead of hexoses. Frangulin (c/. p. 
226) is an example of a pentose derivative, and more recently 
it has been shown that the poisonous hsemolytic substance 
present in the fungus Amanita phalloides is a pentoside. 

Within recent years a considerable number of glucosides have 
been obtained synthetically, some of these being identical with 

1 Feist, Ber., 33 (1900), 2061, 2069, 2091 ; Fraser, ** Strophanthus," 
Edinburgh (1887); Arnaud, 0. B., 107 (1888), 181, 1112. 

232 



VARIOUS OTHER COMPOUNDS OF INTEREST 



233 



natural products. For example, E. Fischer^ has obtained dl. 
mandelonitrile gluooside, identical with prulaurasin ; this has 
been resolved into its dextro and Isbvo components, and the 
former found to be identical with sambunigrin, a glucoside 
occurring in the leaves of the elder. 

Unfortunately, however, the glucosides of greatest importance 
medicinally have not yet been synthesized, and are mostly of 
unkhown structure. For this reason, and owing to the fact that 
very few synthetic derivatives have been prepared from them, 
the glucosides, in spite of their great physiological and practical 
importance, lie rather beyond the scope of this book. 

Camphor and the Terpenes. — ^The substances of the camphor 
group show a general resemblance to one another in their 
physiological action. 




HoC 




HoG 



CH3-C-CH 




CH— OH 



!H. 




^H— OH 



H 

Menthol. 

All three have an antiseptic and slight local ansdsthetic action. 
Borneol, known also as Borneo camphor, has less local irritant 
action, and can be tolerated in larger doses than camphor. 
Menthol is not much used internally, but it finds employment 
as a mild local anaBsthetic. Camphor is the most important of 
these substances, and, as is well known, is obtained from the 
camphor-laurel, growing in China, Japan, and the East Indies, 

^Fischer and Bergmann, Ber., 50 (1917), 1047. 



234 



SYNTHETIC DRUGS 



but within recent years it has also been produced artificially 
from turpentine. 

It is a carminative and is used to check colds in the head, 
Mid for a very laige variety of other medicinal purposes. It is 
injected as a stimulant in cases of collapse. 

It is necessary to distinguish between the so-called " artificial " 
or " synthetic camphor," and true camphor produced artificially. 
The former is in reality not camphor at all, but is "pinene 
hydrochloride," obtained by the action of dry hydrogen chloride 
on turpentine. Turpentine consists chiefly of pinene, and on 
treatment with dry hydrochloric acid, the crystalline ''pinene 
hydrochloride" is formed. This substance, which resembles 
camphor in many of its properties, is bomyl chloride, an intra- 
molecular change taking place when hydrogen chloride acts on 
pinene. 

CHa 



r 




H,C. 



CHr-C— CH, 



HCl 



OH, 



H 

Pinene. 



H,C 



r 




\ 



H,C 



CH,— C— CH, 




Intermediate product, not isolated. 

CH, 

A 



H,C 



CHa 



GSj^ — C— -CHj 



H,C 




Bomyl chloride (" Pinene chloride"). 

I 



VARIOUS OTHER COMPOUNDS OF INTEREST 



235 



Trae camphor has been completely synthesized, but the 
synthesis is an extremely lengthy and laborious one, and is 
impracticable as a commercial process. Camphor can, however, 
be economically prepared from turpentine (pinene) by a simple 
series of reactions. Turpentine on heating with anhydrous 
oxalic acid at 120''-130'' C, yields camphor, borneol, and the 
oxalic and formic esters of borneol.^ 

GH3 CHs 

i 




GH.3 — C — CSg 



HjO 



* HjC 

+H-OH 



,CH 



CH . OH 



CHa— 0— CHa 



2 



C 

H 

Pinene. 




+0 



HjC 



H,C 



CH.3 — C — CH 



OH 



1 



H 
Camphor. 

The borneol esters are hydrolyzed, and the resultant borneol 
oxidized to camphor by means of dichromate and sulphuric 
acid.2 

Various other methods of oxidizing borneol to camphor have 
been devised, using permanganate,^ nitric acid,^ chromic acid,'^ 
air,^ or ozone ^ as the oxidizing agent. 



1 D. B. P., 134,653. 

»D.R. P., 167,690. 

9 Ibid., 161,623, 166,722. 



^Ibid, 220,838; E. P., 21,946 (1907). 
* Ibid., 217,666. » Ibid., 168,717. 

7 Ibid., 161,306. 



236 SYNTHETIC DRUGS 

Valerianic Acid Derivatives. — ^These are used as nervous 
sedatives, and some of them, containing bromine and iodine, 
have already been mentioned in Chapter XIII. 

The esters of borneol and menthol with isovalerianic acid, 

^CH — CHa — COOH, are known as Bornyval and Validol 

respectively. Gynoval is the iso-borneol ester of the same acid, 
and Valyl is the diethyl-amide (CH3)2 . CH . CHg . CO . N(C2H5)2. 
It will be seen that this also contains the grouping — CO.N(C2H5)2 
which is present in many other hypnotic and sedative com- 
pounds. New BornyvaJL is bornyl isovalerylglycoUate, 

(CH!g)2 . CH . CM2 • CO . O — CH2 — CO . O . CjqHj^. 
Qlyceropliospliates. — One of the chief constituents of nervous 
tissue is lecithin, a complex ester of choline and distearylglycero- 
phosphoric acid, the composition of which is indicated by some 
such formula as — 

CH2— O— CO-Ci,H35 



CJH— 0— 



CO — C17H35 

\0H \0H 

In reality if is somewhat more complex, for it contains also the 
corresponding derivatives of various other fatty acids such as 
palmitic, Gy^^E^fi^ and of unsaturated acids such as oleic, 
C^gHg^Os, and linoleio, Cign3202, as well as that from stearic 
acid, CigHggOg. On hydrolysis it yields a glycerophosphoric 
acid which is probably a mixture ^ of the a and p acids — 

CH2— OH CH2— OH 

CH— OH CH— 0— P^H 

CH2--O— P^OH CH2— OH 

\0H 

a-acid. /3-aoid. 

As lecithin is said ^ to exert a favourable influence on growth 
and metabolism, glycerophosphoric acid and its salts have been 

> 0. BaUly, C. -B.. 160 (1916), 396. 

>Danilewski, C. i2., 121 (1896), 1167 ; 123 (1896), 196. 



VARIOUS OTHER COMPOUNDS OF INTEREST 237 

introduced into therapeutics. It is, however, improhable that 
lecithin is built up in the body from glycerophosphoric acid, 
and it is doubtful whether glycerophosphates have any advan- 
tage over the inorganic hypophosphites. 

Glycerophosphoric acid is prepared by the action of phosphorus 
pentoxide on glycerol,^ or by heating phosphoric acid with 
glycerol for six days.^ 

A better result is obtained if the glycerol and syrupy phosphoric 
acid are heated for twenty-four to twenty-eight hours at 100''-105° 
in a vacuum.^ 

Sodium glycerophosphate may be obtained^ by heating two 
molecules of glycerol with one molecule of monosodium or 
monoammonium phosphate in a vacuum, whereby a diglyceryl- 
monometallic phosphate is formed. 

C3H5(OH)3 HO. 

+ \P0— ONa = 



C3H,(OH)3 ho/" 






yjLKJ-^rM^ + 2H2O 



This is then saponified by caustic soda solution, and disodium 
glycerophosphate separates out on concentration. 

The crystalline sodium salt thus obtained has been shown to 
be identical with that of the )3-glycerophosphoric acid obtained 
synthetically,^ and this conclusion as to its constitution has 
been confirmed by an indirect method.^ 

The sodium salt is very soluble in water, the calcium salt 
moderately soluble in cold water, but almost insoluble in hot. 
The ferric salt is^luble, and therefore can be used to combine 
the tonic properties of iron and phosphorus. 

In the preparation of the crystalline sodium salt, there is 
always some uncrystallizable mother liquor, rich in glycero- 
phosphate. This probably contains some of the sodium salt 
of the )Ji-acid. The salts of this acid have been obtained 
synthetically by the action of trisodium phosphate on a-mono- 

1 Pelouze, Joum, prakU Chem,, 36 (1845), 257. 

a Portes, Prunier, Bui, [3] 13 (1895), 96. 

s E. P., 2806 (1912). See also E. P., 2881 (1912), and E. P., 19,319 (1911). 

* French Patent, 873,112. 

«» King and Pyman, J. C. 8., 105 (1914), 1238. 

<>Grimbert and BaiUy, 0, i2., 160 (1916), 207. 



338 



SYNTHETIC DRUGS 



chlorhydrin, CH,C1 . CH(OH) . CH, . OH,i and by the oxidation 
of iaodinm monoallylphosphate.^ 

CHj : CH— CH,— O— PO(ONa)a -> 
CHaCOH)— CH(OH)— CHj— O— PO(ONa)a. 

Bromo-leoithin is said to differ from lecithin in being absorbed 
in the intestine as such, without being split up into glycero- 
phosphoric acid. It is prepared by saturating a chloroform 
solution of lecithin with bromine and drying in vactio.^ lodo- 
lecithin has also been prepared.^ 

Sulphur Compounds. — In this section are included various 
compounds containing sulphur. For the most part, they are 
not related to one another, but are brought together here for 
convenience. 

Ichthyol is one of the best known of these. It is a substance 
of unknown composition, containing sulphur, obtained by the 
destructive distillation of "stink-stone" or "oil-stone," a de- 
posit of fossil fish found in the Tyrol and southern Bavaria. 
By the action of sulphuric acid on the volatile basic oil thus 
produced, a sulphonic acid is formed, the salts of which are 
used medicinally. The ammonium salt of this ichthyol-sulphonic 
acid is a reddish-brown syrup, soluble in water, and is often 
known simply as " Ichthyol." It is used both externally and 
internally for skin diseases, and is also used internally in tuber- 
culosis and many other complaints, and as an intestinal anti- 
septic. The lithium and sodium salts are also used, and the 
zinc salt is used externally. 

The disagreeable smell and taste of ichthyol are said to be 
largely due to impurities, and it can be obtained in a purer 
form by steam distillation in a vacuum.^ 

Ichthalbin is an odourless and tasteless powder, obtained by 
precipitating an albumen solution with a solution of ichthyol- 
sulphonic acid.* It is used in the treatment of eczema and of 
intestinal catarrh. A compound of ichthyol-sulphonic acid and 
formaldehyde,^ is known as Ichthoform. It is a dark coloured 
powder insoluble in water, and with very little taste or odour. 



^ King fluid Pymflkn, los, dt, 
»D.R. P., 156,110. 
BJ&id., 118,452. 
' Ibid., 107,238. 



SO. BaiUy, C. 12., 160 (1915), 163. 
«IM<i., 155,629. 
>J6«d., 100,707, 124,144. 



VARIOUS OTHER COMPOUNDS OP INTEREST 239 

It is used internally as an- intestinal antiseptic, and externally 
as a dressing for wounds (iodoform substitute). 

Triphenylstibine sulphide, (C6H5)3 SbS, is used under the 
name of Sulphofqrm in skin diseases as it liberates nascent 
sulphur on the skin. 

C3H,-NH. 
AUyl-thiourea, /OS, known as Thiosinamine, is 

nh/ 

a substance of some importance as a drug. It is formed by the 
action of ammonia on allyl-mustard oil, 

C3H5- N:G:S +• NH3 - C3H5 . NH . OS . NH^, 

and is a white crystalline substance moderately soluble in water. 
It is administered by hypodermic injection for. the treatment of 
lupus, and for softening scar-tissues. Its sparing solubility in 
water is a drawback, and more concentrated solutions can be 
obtained by dissolving it with half a molecular proportion of 
sodium salicylate.^ This solution is known as Fibrolysin, and 
it is claimed that the presence of the sodium salicylate not only 
increases the solubility, but also renders the injection less 
painful. It has been extensively used in relaxing scar-tissue. 
The additive compound of thiosinamine with ethyl iodide, 
C3H5 . NH . OS . NH2, C2H5I, is known as Tiodine, and is 
readily soluble in water giving solutions said to be painless on 
injection. lodolysin is a similar soluble, non-irritant prepara- 
tion of thiosinamine. It' is said to contain 43 per cent, of 
thiosinamine, and 47 per cent, of iodine. 

Becently successful results have been claimed for a sulphur 
compound in the treatment of syphilis.^ This is di-o-amino- 
phenyl disulphide, 

NH2 NH2 

— ^ 



Cr 




known as Intramine, It is obtained by the oxidation of ortho- 
aminophenyl mercaptan with ferric chloride, and is a pale 
yellow crystalline compound insoluble in water. It is admin- 
istered by intramuscular injection of a suspension in olive oil. 

^ D. B. P., 163,804. s MoDonagh, Laticet, 190 (1916), 288. 



INDEX. 



AOXTAIiDBHYDB, 28, 51. 

Acetanilide, 67, 68. « 
Acetomorphine, 110. 
Acetone, 59. 

— behaviour of, in organism, 38. 
Acetone-ohloroformfsee Ohloretone). 
Aoetophenone (see Hypnone). 
Aoetopyrine, 66, 157. 
Acetoxime, 26. 
Aoetozone, 190. 

/-Acetylamino-phenol, 70, 78, 164. 
Aoetylamino-phenol acetamide, 77. 
Acetylamino-phenyl benzoate, 77. 
Acetyl-atoxyl, 204-205. 
Aoetyl-ethylamino-phenyl acetate, 77. 
Acetyl - p - hydrozyphenylethylamine, 

148. 
Acetyl-salicylic acid, 157, 158. 

esters of, 168. 

Add groups, effect of, 29. 

Aoitrin, 224. 

Aoriflavine, 173. 

AdaUn, 129. 

Adrenaline, 34, 129-U6, 141, 150. 

— methylene and methyl ethers of, 

188-135. 

Mo-Adrenaline, 134. 

Adrenalone, 131, 147, 149-150. 

Agurln, 217. 

Airol, 173, 178, 183. 

Albargin, 194. 

Alcohol (see Ethyl Alcohol). 

Alcohols, primary, secondary, and 

tertiary, action of, 
23, 55, 56. 

behaviour of, 

organism, 38. 

Aldehyde groups, effect of, 28. 

Alizanne-Bordeauz, 226. 

Alkyl groups, effect of, 17, 19. 

N-Alkyl quinoline derivatives, 64. 

Allyl-thiourea, 208, 239. 

Allyl-tri-methyl -ammonium hy 
droxide, 32. 

Aloe, 225. 

AloXn, 227. 

Alum, 195. 



Aluminium compounds, 195. 
Alumnol, 195. 
Alypine, 99, 100. 

Amidopyrine (see Pyramidon), 66. 
Amino-aoetic acid (see Glycine). 
Amino-aceto-catechol, 1^. 
Amino-acetopyrogallol, 150. 
Amino-acetoveratrone, 119, 120. 
Amino acids, 38, 39, 42, 138. 
m- Amino-benzoic add, 30. 
p-Amino-benzoic acid, derivatives of, 

102-103. 
7-Amino-butyric add, 79. 
Amino-ethanolcatechol, 149. 
Amino-ethyl-catechol, 149. 
Amino-ethyl-pyrogallol, 149. 
Amino-hydroxy-benzoic acid, esters 

of, 100, 101. 
l-Amino-naphthalene-4 andnio acid, 

206. 
8-Amino-naphthol (l)-3-6 disulphonio 

add, 172. 
8-Amino-paraxanthine, 219. 
p-Amino-phenol, 36, 68, 70, 71-77. 
p-Aminophenyl-areenious oxide, 201, 

209. 
p-Amino^phenylarsine, 209. 
5f«-|>-Ammophenylarsinic add, 205. 
JT-Aminophenylarsinic add (see also 

Atoxyl and Arsanilic Add), 203. 
p-Aminophenylstibinic add, 215. 
8-Amino-theophylline, 219. 
Amino-tolyl-arsinic acids, 205, 206. 
6t«-2-Amino-tolyl-5-arBinio add, 205. 
8-Amino-valerii^c acid, 79. 
Ammonium bases, effect of, 5, 15. 
Amphotropin, 177. 
Amygdophenine, 75. 
Amylamine, 147. 
Mo-Amylamine, 137. 
Amylene, action of, 19. 
— hydrate, 56. 
tertiary Amyl-urea, 56. 
AnsBsthesine, 102. 
Anchoring grou|Rff, theory of, 6, 7, 10, 

11, 171. 
Aniline, 63, 67-68* 

241 1 6 



m 



242 



SYNTHETIC DRUGS 



Aniline, oaddatioa of, in organiim, 

88,68. 
Anido add, 90. 
— aldehyde, 189. 
o-Anisidine, 166. 
AnthzagaUol, 226. 
Anthranil axsioio add, 206. 
Anthiapoxpurin, 222, 227. 
Anthxaquinone derivativee, 226-227. 
Antifebrin (see Acetanilide). 
Antiluetan, 216. 

Antimcmy oompounds, 214-216. 
^ finely divided metallic, 216. 
Antipynne, 20, 66. 66. 
Antithennin, 67. 
Aperitol, 228. 
Apocodeine, 111, 112. 
i^-Apooodeine, 111. 
Apoxnorphine, 107, HI. 
Azeoaidine, 11. 
AreooUne, 11. 
Argentandn, 194. 
Aigonin, 194. 
Aristol, 184. 
Aiistoquinine, 84. 
Arrhexial, 208. 
Arsacetin, 200, 204, 208. 
Anaxnin, 204. 
Arsanilio add, 204, 205, 208 (eee also 

Atozyl). 
AneniouB oxide, 197. 

aromatic derivatives of, 201. 

1-1-Arsenoanthranol, 218. 
Arsenobenzene derivatives, 201, 202, 

209. 
Anenobensol (see Salvarsan). 
Arsenophenol, 209. 
Arsenophenylglycine, 209. 
Arsenostibino oompoimds, 215. 
Arsinic adds, 208, 208. 
Arsoninm bases, 16, 17. 
Aryl-stibinio adds, 216. 
Aseptol, 164. 
Asparagine, 84. 

Aspirin (see Aoetyl-salioylio add). 
Asterol, 198. 
Atophan, 228. 
Atozyl, 197, 198, 199-201, 203-204> 

208. 
Atrolaotinic add, 89. 
Atropine, 12, 84, 86, 88, 89. 

Baoijoni*b theory of narcosis, 49. 

BarbaloXn, 226. 

Barbitone (s. Veronal), 67. 

Bart*s reaction, 208, 216. 

Basic nitrogen groups, effect of, 26. 

7n-Ben9aminosemicarbaiide, 67. 



Bennnilide, 68. 

Bensene, bdiavionr of, in onanism, 
89. 

— hydrocarbons, action of, 19. 
Benddine dyes, 171, 172. 
Benioic add, behaviour of in organ- 
ism, 42. 

Bensonaphthol, 168. 
Beniophenone, 69. 
Bensosalin, 168. 
Bensosol, 167. 
Bensoyl-ecgonine, 92. 

esters of, 92, 98. 

Bensoyl-phenjrleth^lamine, 189. 
Bensoylsalicylic acid, methyl ester of, 

168. 
Bensyl-morphine (see Peronine). 
Berberine, 116, 123-124. 
Betol, 16& 
Biogen, 190. 
Bismuth, 178. 

— emetine iodide, 128. 
Bleaching powder, 179. 
Boric add, 190. 
Bomeol, 288, 2S5. 286. 

— carbonate, 166. 

— esters of, 286. 
Bomyl chloride, 284. 
Bom^rval, 286. 
Brilliant green, 172. 
Bromalbin, 189. 
BronuJ hydrate, 46, 47, 56* 
Bromdiethylacetyl-urea, 189. 
Brometone, 64. 
Bromides, alkaline, 188. 
Bromipin, 188. 
Bromoform, 51, 182. 
Bromoglidine, 189. 
a-Bromo-isovalerianic add, 189. 

bomeol ester, 189. 

Bromo-ledthin, 288. 
Bromo-phenacetin, 76. 
Bromunl, 189. 
Brovalol, 189. 
Butyl-chloral, 64. 

hydrate, 46, 47. 

tertiary Butyl-urea, 66. 

Oaoodtl, 202. 
Gacodyliaool, 167, 208. 
Gacodylic add, 202. 
Gadaverine, 147. 
Oaffdne, 18, 217* 

— acetylamino derivatives of, 217. 
iso-Oaffdne, 219. 
Calomel, (see Mercurous chloride). 

tOamphor, 174, 233-235. 
Ganadine, 116, 



INDEX 



243 



Carbamio add, 26. 
" Carbon," 174. 
Garbon-tetraohloride, 24, 51* 
Oarvone, 82. 
Gascara, 225. 
Catechol, 20, ISO, 164. 

— carbonate, 166. 
Cephaeline, 127, 128. 

Changes in the organism and their 
relation to' the activity of a drug, 
12, 13. 

Ohemioo-therapy, 170, 174, 197. 

Ohinosol, 175. 

Chloracetyl-cateohol, 181. 

Chloral, 51. 

— behaviour of in organism, 87, 89, 

41. 
Chloralamide, 58. 
Chloramine antiseptics, 179-181. 
Chloramines, 179-181. 
Chloramine-T, 180. 
Chloral-ammonia, 58. 
Chloral-formamide, 58. 
Chloral-hydrate, 46, 47, 51, 52. 
Chloral-imide, 58. 
ChlonJ-urethane, 54. 
Chloioosane, 181. 
Ohloretone, 54. 
Chlorine compounds, 179-181. 
1-Chloro - 2 amino - phenyl • 5 arslnio 

add, 206. 
Chloroform, 24, 50, 172. 
S-Chloro-theophylUne, 219. 
Choline, 82. 
Chrysophan, 225, 282. 
Chxysophanic add, 225, 227. 
Cinchonine, 82, 88, 84. 
Cinnamic acid, 159. 
Citarin, 228. 

Citric add derivatives, 177, 228. 
Cocaine, 2, 11, 35, 86, 91, 92, 93, 94, 

186. 
a-Cocaine, 2, 85, 96. 
Codeine, 104, 105-109, 120. 

— methyl bromide, 110. 
CodethyUne (see Ethylmorphine). 
Collidine, 38. 

CoUddal mercury, 192. 

— ttlver, 194. 

chloride, 194. 

Coniine, 80. 

Cordal (see Tribromsalol). 

CorydaUne, 116, 126. 

Cosaprin, 69. 

Cotamine, 116, 122, 123, 125, 126, 

127. 
Coto-bark, 230. 
Cotoln, 281. 



o-Coumaric add, 169. 
Creolin, 152. 
Creosoform, 169. 
Creosol, 164, 165. 

— carbonate, 166. 
Creosote-carbonate, 166. 
Creosote-phosphite, 167. 

0-, m- and j7-Cresols, 152, 158, 159. 

Cresotinic add, 153, 167. 

Cresylic add, 153. 

Croton-dl, 212. 

Crum Brown and Fraser, law of, 5, 

80. 148. 
Cryogenin, 67. 
Cryptopine, 128. 
Cupreine, 82, 84. 
Curare, 5, 148. 
Cyanaoetic add, 28. 
Cyanogen chloride, 28. 

— radicle, effect of, 28. 
Cyclic urddes, 57. 
Cycloform, 102. 
Cystamine, 176. 
Cystazol, 177. 
Cystogen, 176. 
Cystopurin, 177. 

Dakin's solution, 179. 
Dermatol, 178. 
Dextroform, 176. 
Diacetin, 46, 47. 
Diacetonamine, 97^ , 
Diaoetyl-morphine, 109, 110. 
Diacetyl-phenetidine, 74. 
p-Diamino-arsenobensene, 209. 
2>-Diamino - dihydrozyarsenobenzene, 

209. 
8-d-D i a m i n o.4-4'-dihydrozystibino- 

benzene, 215. 
Di-o-aminophenyl disulphide, 289. 
«2/m-Diamyl-urea, 56. 
Diaspirin, 157. 
Dichloramine-T, 180, 181. 
Diethylamine, 102, 108. 
Diethylaminoethyl alcohol, esters of, 

102, 103. 
Diethyl-barbiluric acid (see Veronal). 
Diethyl-ketone, 59. 
Diechyl-malonylurea (see Veronal). 
Diethyl-sulphone-methane, 46. 
Digitalin, 282. 
Digitalis, 232. 
Digitozm, 282. 
Dihydro-papaverine, 118. 
2-4-D i h y d r o X y-o)-amino-acetophe- 

none, 149. 
Dihydioxy-d i a m i n o-arsenobeosene, 

202, 210-214. 

16  



244 



SYNTHETIC DRUGS 



2-4-Dihydiozypheiiylar8inic acid, 213. 
3-4-I>ihydroz7ph6nylethylainine, 138, 

139, 140, 141, 142, 149, 150. 
3 - 4 - Dihydro^phenylethylinetbyl • 

amine, 141, 142, 149, 150. 
DihydxozypiperaBine, 222. 
4-5-I)imetiioxy-2^-methylaminoethyl- 

benzaldehyde, 126. 
6-7-Diinethozy-2-methyl-3-4-dihydro- 

iaoqainolimum chloride, 126 (see 

Lodal). 
6 - 7 - Dimethozyifloquinoliiie - 1 - car- 

bozylic add, 127. 
4-Dimethyl-amino-aiitipyrine (see 

Pjrramidon). 
1 - 4 -Dimethyl - 2 -amino -phenyl -5- 

andnic acid, 206. 
p-Dlmethytamino-phenylarsinic acid, 

207. 
Dimethyl-pipeiazine, 222. 
Dimethyl - sulphone - diethylmethane 

(** reversed " sulphonal), 60. 
Dimethyl - sulphone - dimethyl - meth- 
ane, 46. 
Dimethyl - sulphone - ethyl - methane, 

60. 
Dimethyl - sulphone - methyl - ethyl - 

methane, 60. 
Dionine 110 (see also Ethyl-mor- 
phine). 
Diphenyl, 19. 

— tartrate, 220. 
Diplosal, 157. 
Dipropyl-malonyl urea, 57. 
Disalol, 163. 
Dispermin, 222. 
Distribution coefficient, 46. 
Diurotin, 217. 
Dormigene, 189. 
Dormiol, 53. 

Dulcin, 21. 
Ductal, 165-167. 
Dyestuffs, 7, 170-174. 

ECGONINB, 88, 91, 92. 

— methyl ester, 92, 93. 
a-£ogonine, 95. 

Ehrlich's theory of the action of 

drugs, 6, 7, 170, 171-174. 
Ektogen, 190. 
Emetine, 127, 128. 

— bismuth iodide, 128. 
Emodin, 225. 
Epicarine, 154. 

Epinephrine, 129, 136 (see also 

Adrenaline). 
Epinine (see 3-4-Dihydrozyphenyl- 

ethylmethylamine). 



Epiosine, 116. 
Ergamine, 139. 
Ergot, 129, 137. 
Ergotoxine, 138. 
Ericin, 162. 

Eirthrol-tetranitrate, 25. 
Ether (see Ethyl ether). 
p-Ethozyphenyl urethane, 75. 
Ethyl alcohol, 23. 
Ethylamino-acetocatechol, 149. 
Ethylamino-ethylcatechol, 149. 
Ethyl antimony! tartrate, 216. 

— bromide, 50, 51. 

— chloride, 50, 61- 
Ethylene-chlorhydrin, 102, 103. 
Ethylene-dibromide, 51. 
Ethylene-diethyl sulphone, 60. 
Ethyl ether, 51, 55. 
Eth^lidene diethyl sulphone, 60. 

— cUmethyl sulphone, 60. 
Ethylmorphine, 109, 110. 
NEthyl-phenacetin, 73. 
(di)-Ethyl pmacone, 59. 

a Ethyl piperidine, 80. 
Ethyl-propyl-malonyl urea, 57. 
Ethyl salicylate, 162. 

— urethane, 46, 47, 58. 
Eubomyl, 189. 
a-Eucaine, 96, 97, 134. 
3-Eucaine, 97, 98, 134. 

— lactate, 97. 
Eucodeine, 110. 
Euool, 167. 
Eugenol, 162. 
ifo-Eugenol, 167. 
Eugenol carbonate, 166. 

— methyl ether, 141. 
Euphorin, 69, 75. 
Eupyrin, 76. 
Euquinine, 84. 
Euresol, 153. 
Europhen, 184. 
Eusol, 179. 
Exalgin, 69. 
Ezodin, 227. 

Febbipybxn, 195. 
Pibrolysin, 239. 
Flavine derivatives, 173-174. 
Flavopurpurin, 226. 
Formaldehyde, 15, 175, 176, 177. 
Formamint, 176. 
Formanilide, 68. 
Formurol, 177. 
Forto![n, 231. 
Fowler's solution, 197. 
Frangulin, 226, 232. 
Fumaric acid, 33, 34. 



INDEX 



245 



GALLACDTOPHlBNOMfi, 41. 

Gallic acid, 177. 
Galyl, 212. 
Gentdsimc add, 40. 
Gluoosides, 1, 232. 
Glutei, 176. 
Glycerol, 21, 162. 

— esters of, with salicylic acid, etc., 

162. 
Glycerophosphoric acid, 286-287. 
Glyceryl ether, 22. 
Glycine, 42, 48. 
Glycosal, 162. 
Glycuronic acid derivatives, 40, 41, 

42. 
Grey oil, 191. 
Griserin, 186. 
Guaiacetin, 169. 
Guaiacol, 20, 155, 164-165. 

— cacodylate, 167, 208. 

— carbonate, 165. 

— carbozylic'acid, 169. 

— esters of, 167. 

— phosphite, 167. 
Guaiamar, 164. 
Guaiaperol, 168. 
Guaiathol, 165. 
Guanidine, 26. 
Gynoval, 236. 

"H "-ACID, 172. 

Hsematogen, 196. 

Haemoglobin, 195. 

HflBmol, 195. 

Halasone, 181. 

Halogen in organic compounds, effect 

of, 28. 
Hectine, 208. 
Hedonal, 58. 
Helmitol, 177, 228. 
Hemisine, 186 (see also Adrenaline). 
Hermophenyl, 198. 
Heroin, 110 (see also Diacetyl-mor- 

phine). 
Hetooresol, 159. 
Hetol, 159, 208, 217. 
Hezamecoll, 169, 176. 
Hezamethylenetetramine, 176-177) 

222-228. 
Hezamine, 176, 177. 
Hexaminoarsenobenzene, 218. 
Hexylamine, 147. 
Hippuric aoid, 42, 220. 
Histamine, 189. 
Histidine, 188. 
Holooaine, 98. 
Homatropine, 90. 
Homogentisinic add, 40. 



Homoprotocatechuic acid, 120. 
Homoveratraldehyde, 141. 
Homoveratric add, 120. 
Homoveratroyl chloride, 119-120. 
Hordenine, 144» 148. 

— methiodide, 144, 148, 150. 
Hydracetin, 67. 
Hydrargol, 192. 
Hydrargotin, 198. 
Hydrargyrol, 198. 
Hydrastine, 116, 123. 126. 
Hydrastinine, 126, 127. 
Hydrazine, 8, 26. 
Hydrazoic acid, 26. 
Hydrocarbons, action of, 17. 
Hydrocyanic acid, 15. 
Hydrogen peroxide, 190. 
Hydropyiin, 157. 
Hydroquinone, 89, 162. 
p-Hydroxy - w - amino - acetophenone,« 

148, 144. 
m- and j>-Hydroxybenzoic acids, 156. 
o-Hydroxybienzoic add (see Salicylic 

acid), 
m- Hydroxy-benzoyl- tropeine, 89. 
2)-Hydroxy - w - chloro - acetophenone, 

144. 
Hydroxylamine, 26. 
Hydroxyl groups, effect of, 21-28. 
p-Hydroxy-phenylacetonitrile, 182. 
p-Hydroxy-phenyl-arsenious oxide, 

201. 
p-Hydroxy-phenyl-arsinic acid, 202, 

206, 207, 209, 210. 
p-Hydroxy-phenylethanolamine, 148. 
o-Hydroxyphenylethylamine, 149. 
27-Hydroxyphenylethylamine, 129, 

136, 187, 138, 130, 148. 
p-K y d r o X y phenylethylethylamine, 

145. 
p -Hydroxyphenylethylmethylamine, 

144-145. 
p-Hydroxyphenyl-urethane, 75. 
o-Hydroxy-/5-2-p3rridyl-propionyl-tro- 

peine, 89. 
Hyoscyamine, 84, 86 (see also Atro- 
pine). 
Hypnal, 54. 
Hypnone (acetophenone), 29, 59* 

— behaviour of in organism, 41. 
Hypodermic purgative (see Apooo- 

deine). 

ICHTHALBIH, 288. 

Ichthoform, 288. 
Ichthyol, 288. 

/3-Iminazolyl-ethylamine, 138. 
Indophenol reaction, 72. 



246 



SYNTHETIC DRUGS 



Indozyl, formation ol in organism, 39. 

Intramine, 239. 

lodalbin, 187. 

Iodides, alkaline, 186. 

lodipin, 187. 

lodival, 187. 

p-Iodo-aniline, 204. 

Iodoform, 181. 182-184, 186. 

lodofoimal, 182. 

lodoformin, 182. 

lodoglidine, 187. 

j>-Iodo-guaiaoal, 187. 

lodol, 183. 

lodo-lecithin, 238. 

lodolysin, 239. 

lodophenol, 184. 

lodo-thyrine, 187. 

jT-Iodoxy-anisole, 185. 

Ionization, effect of, 16, 17. 

Iron, derivatives of, 195 196. 

Isoform, 185. 

Isomerism, effect of, 33. 

Isomorphous groups, behaviour of, 16. 

Jalap, 228. 

Kaibinb (hydroxy - N - ethyl • tetra - 
hydro-quinoline), 64. 

Kairoline A (N • ethyl - tetrahydro- 
quinoline, 64. 

— B (N - methyl - tetrahydro - quino- 
line), 64. 

Kalmopyrin, 157. 

Ketones, effect of, 29, 59. 

Kharsivan (see Salvarsan). 

Lactophenin, 74. 
Jliactyl-aminophenol, 164. 
Lactyl-aminophenyl-ethyl-carbonate, 

77. 
** Ladenburg's Bule," 89. 
Lambkin's cream, 191. 
Laudanine, 105. 

Laudanosine, 104, 105, 121, 126, 127. 
Laxin, 228. 
Lecithin, 236-237. 
Leucine, 137. 
Liminal values, 46. 
Lithium salts, 220. 
Lodal, 127, 141. 
Loew's theory of poisons, 8. 
Loretin, 186. 
Losophan, 185. 
Luargol, 213. 
Lutidine, 33. 
Lysetol, 222. 
Lysidin, 222. 
Lysol, 152, 163. 



MAONXBiUM-perhydrol, 190. 

Malachite green, 172. 

Malakin, 76. 

Malarin, 76. 

Maleic acid, 33, 34. 

Malic acid, antimony derivatives of, 

216. 
Mandelic acid, 89. 
Mandelonitrile glucoside, 238. 
Maretin, 67. 
Martins yellow, 29. 
Meconine, 122, 
Medinal, 57. 
Menthol, 166, 167, 233. 236. 

— carbonate, 166. 

— salicylate, 163. 
Menthone, 32. 
Mercuric chlor de, 17, 191. 

— cyanide, 17. 
Mercurous chloride, 17. 
Mercury, coUoideJ, 192. 

— derivatives of, 191-193. 

— organic derivatives of, 192-193. 

— tannate, 193. 
Mesotan, 162. 
Metaldehyde, 28. 
Methacetin, 70, 78. 
Methane, 18, 50. 
p-Methoxyphenylethylamine, 139, 

145. 
p - Methoxyphenyl - trimethylammo - 

nium iodide, 145. 
Methoxy-quinoline, 63. 
Methoxy-tetrahydroquinoline, 68. 
Methylacetanilide (see ExaJgin). 
i9-Methyl-adrenaline, 135. 
Methylaminoacetocatechol (see Ad- 

renalone). 
Methylamino-ethyl-oatechol, 149 (see 

also 3 - 4 - Dihydroxjrphenylethyl- 

methylamine). 
a-Methyl-anthraquinone, 225. 
N-Methyl-cephaeline, 128. 
Methyl-chloride, 24, 50. 
Methyl-chloroform, 51. 
N-Methyl-emetine, 128. 
Methylene blue, 171, 173. 
Methylene-oitric acid, 177. 
Methylenecitrylsalicylic acid, 157. 
Methylene-dichloride, 24, 50. 
Methylene-diethyl-sulphone, 60. 
Methylene-dimethyl-sulphone, 60. 
Methylene-hippuric acid, 200. 
Methyl- ethyl ether, 51. 
Methyl-ethyl pinacon^, 59. 
Methyl-isoeugenol, 184. 
2-Methyl-pheno-morphoUne, 115. 
Methyl-phenyl •pyrazolone, 20. 



INDEX 



247 



Methyl-pinaoone, 69, 
N-Methyl-pyrrolidine, 83. 
Methylrhodin, 163. 
Methyl salicylate, 162. 

behaviour of in organism, 41 

(see also Oil of wintergreen). 
N- Methyl triaoetone-alkamine, 90, 

96. 
Methyl-urethane, 46, 47. 
N-Methyl-vinyl-di acetone - alkamine, 

90,91. 
Meyer's theory of narcosis, 45-46. 
Microcidin, 154. 
Mitscherlich's law, 16. 
Molecular weight, effect of, 33. 
Monacetin, 46, 47. 
8-Monomethyl-xanthine, 13, 14, 219. 
7-Monomethyl-zanthine, 219. 
Moore and BoaJPs theory of narcosis, 

48-49. 
Morphigenine, 116. 
Morphine, 104, 105-109. 110-112, 115, 
121. 

— aoyl derivatives of, 109, 110. 
Morphine-sulphuric acid, 6, 10, 29. 
Morpholine, 112-115. 

Naqa red, 172. 

Naphthalene, 19, 170. 

a-Naphthol, 154. 

i9-Naphthol, 154. 

Naphthol-carbozylic aoids, 157, 158. 

iS-Naphthol salicylate, 163. 

Naphtholsalol, 163. 

Naphthol yellow S, 29. 

iS-Naphthylamine, 78. 

fi • Naphthylamine - 3 - 6 - disulphonic 

acid, 172. 
Narceine, 104, 124-125* 
Narcosis, theories of, 44-49. 
Narootine, 104, 105, 116, 117, 121, 

122 123. 127. 

— methochloride of, 125. 
Nargol, 195. 

Neo-kharsivan (see Neo-salvarsan). 
Neo-salvarsan, 211-212. 
Neurine, 32. 
Neurodin, 75. 
New bomyval, 236. 
New-oacodyl, 203. 
New-orthoform, 101. 
New-urotropin, 177. 
Nicotine, 34, 80, 83, 148. 
Nirvanine, 101. 

Nitriles and isonitriles, effect of, 28. 
Nitrites, physiological action of, 25. 
Nitro and nitroso groups, effect of, 
24-25. 



Nitro-bensaldefaydes, behaviour of in 

organism, 39. 
j>-Nitrobenzoic acid, 25, 29. 
Nitro-glycerin, 25. 
2>-Nitrohippuric acid, 25. 
Nitro-phenacetol, 115. 
o-Nitrophenol, 165. 
|7-Nitrophenol, 70. 
o-Nitrophenylpiopiolic acid, 39. 
Nitroso-piperazine, 221. 
jp-Nitrotoluene, 25. \ 
Nisdn (see Zinc sulphanilate). 
Nosophen, 185. 

Novarsenobenzol (see Neo-salvarsan). 
Novaspirin, 157. 
Novatophan, 224. 
Novocaine, 102, 103. 

Oni of wintergreen, 162, 166. 
Orexin, 229-230. 
Orsudan, 205. 
Orthin, 67. 
Orthoform, 100. 
Osmotic permeability, 48. 
Overton's theory of narcosis, 45-47. 
Oxalic aoid, 4, 83. 
Ozynarcotine, 104. 

PaonoIi, 41. 

Papaverine, 104, 106, 116, 117-120. 
121. 

— methochloride of, 121. 
Paraldehyde, 28. 
Paraxanthine, 13, 14, 217-218- 

— 8-amino-, 219. 
Parvoline, 33. 
Pentabrom-phenol, 154. 
Pentachl6r-phenol, 154. 
Pentamethylene-diamine, 79. 
Perborax, 190. 
Perhydrol, 190. 
Peristaltin, 228. 
Peronine, 110. 

" Pharmacophore,** 7. 
Phenacetin, 5, 70. 71, 72, 73. 
Phenanthrene, 104, 106, 115. 
1>-Phenetidine, 70, 71, 72. 

— derivatives of, 74-76. 
Phenocoll, 76. 
Phenol, 21, 152, 192. 

— behaviour of in organism, 40. 

— formation from benzene in organ- 

ism, 39. 
Phenolphthalein, 185. 228. 
Phenyl-alanine, 38, 137. 
p-Phenylene-diamine, 9. 
Phenylethanolamine, 143, 147. 
Phenylethyl alcohol. 145. 



24^ 



SYNTHETIC DRUGS 



Phenyleihylamine, 187, 147. 
Phenyl-etnyl ketone, 59. 
Phenylglyome-arsinio aoid, 201, 202, 

207. 

PhenylhydxaBine, 8. 

2-Pheny]qainoliiie-4-carboxylio acid, 
228-224. 

Phenyl-sulphuiic acid, 29, 40, 154. 

Phenyl-urethane (see Europhen). 

Phesin 74. 

Phloroglacinol, 158-154. 

Phosgene, 165. 

Phosphatol, 167. 

Phosphonium bases, 15, 17. 

Phosphorus, action of yellow and red, 
3. 

Phthalio acid, behaviour of in organ- 
ism, 88. 

Phthatimide, behaviour of in organ- 
ism, 88. 

Picoline, 88. 

Picric acid, behaviour of in organism, 
89. 

Picropodophyllin, 228-229. 

Pilocarpine, 88, SI. 

wo-Pilooarpine, 88, 81 • 

Pinaoones, 59. 

Pinene, 284, 285. 

** Pinene hydrochloride,*' 284. 

Pipecoline, 80. 

Piperasine, 220, 221i 222. 

— quinate, 222. 
Piperidine, 78, 79, 228. . 
•— tartrate, 228. 
Piperidone, 79. 
Piperonal, 182, 188. 
Podophyllin, 228. 
Podophyllinic acid, 228229. 
Podophyllotoxin, 228. 
Potassium ferrocyanide, 16. 

— sulphocyanide, 28. 
Proflavine, 178. 

Propiolp (see Diethyl ketone). 
Propylamino-acetocatechol, 149. 
Propylamino-ethylcatechol, 140. 
Protargol, 194. 
Protboatechuic aldehyde, 182. 

— acid, 180. 

behaviour of in organism, 41. 

Protopine, 128. 
Protosil, 194. 
Prulaurasin, 288. 
Purgatin, 227. 
Purgatives, 225-229. 
Purgatol, 227. 
Purgen, 228. 
Purpurin, 226. 
Purpurozanthin, 226. 



Pyramidon, 66. 
Pyrajitin, 74. 
Pyrazole, 64-65. 
Pyridhie, 38, 78, 106. 

— behaviour of in organism, 43. 
PyrogaUol, 158. 

Pyrrol, 19, 106, 183. 
Pyrrolidine, 83. 
a- Pyrrolidine, 79. 

QuiNAirOBM, 85. 

Quinaphenin, 84, 85. 

Quinaphthol, 85. 

Quinasoline derivatives, 229-280. 

Quinic acid, 219-220. 

Quinine, and its derivatives, 81-85. 

Quinoline derivatives, 175, 228-224. 

Quinone, 89. 

Quinotropin, 228. 

BnAonviTY, connection between 

toxicity and, 8. 
Besacetophenone, 41. 
Besorcinol, 20, 158. 

— diacetate, 158. 

** Beversed " sulphonal, 60. 
Rh^nose, 226. * 

Rheum (rhubarb), 225. 

Saoohabin, 9, 85, 180. 
Safrole, 81. 
uo-Safrole, 82. 
Salacetol, 168. 
Salicin, 159, 232. 
Salicyl-acetic acid, 157. 
Salicyl-amide, 164. 
Salicyl-anilide, 68. 
Sallcyl-arsinic acid, 206. 
SaUcylic acid, 158, 155, 156, 220. 

— behaviour of in organism, 40. 
Salicylide, 50. 
Salicylosalicylic acid, 157. 
SaJicyl phenetidine, 75. 
Salicyl-tropeine, 89. 
Saliformin, 223. 

Saligenin, 159, 220. ' 

Salimenthol, 168. 

Salit, 163. 

Salocoll, 77. 

Salol, 156, 160-162. 

Salophen, 164. 

Salvarsan, 202, 210, 214. 

Sambunigrin, 238. 

Scarlet red, 173. 

Schmiedeberg's rules on the action of 

aliphatic compounds, 17. 
Senna, 225. 
I Serum therapy, 170-171. 



' 



INDEX 



249 



Sidonal, 222. 

Silver compounds, 19S-194. 

Soamin, 204. 

Sodium ferrocyaDide, 28. 

— hypochlorite, 179. 

— nitroprusBide, 28. 

— phenate, 156. 

— phenyl carbonate, 157. 

— platinicyanide, 28. 
Sodium-Balvarsan, 218. 
Sodiump-toluenesulphonchloramide, 

180. 

Soluble aspirin, 157. 

Solurol, 223. 

Solveol, 168, 169. 

Somnal, 54. 

Somnof orm, 50. 

Spatial configuration, effect of, 15. 

Spirosal, 168. 

Stereo-isomerides, action of, 8, 83. 

Stibinic acids, 215. 

Stovaine, 99. 

Strophanthidin, 282. 

Strophanthin, 232. 

Strophanthus, 282. 

Stcvchnine, 12, 81. 

Sty|)ticine, 126. • 

Styptol, 126. 

Subcutin, 102. 

Succinylsalicylic acid, 157. 

Sujphoform, 289. 

Sulphonal, 46, 47, 59, 60, 61. 

j>-Sulphondichloramino-benzoic acid, 
181. 

Sulphones, 59-62. 

Sulphonic esters, formation of by 
organism, 40. 

Sulphonium bases, 15, 17. 

Sulphur compounds, 238, 289. 

Suprarenine, 129, 136 (see also Ad- 
renaline). 

Sympathomimetic action, 129, 146. 

Tannic acid, 177, 178, 220. 
Tannigen, 177. 
Tannoform, 177. 
Tartar emetic, 197, 216. 
Terpenes, 233-235. 
Tetrabromcresol, 155. 
Tetrachlorphenol, 154. 
Tetra-ethylammonium iodide, 147. 
Tetrahydro-naphthalene-morpholine, 

113, 114. 
ac-Tetrahydro-/3-naphthylamine, 27, 

78, 147. 
Tetra-iodo-phenolphthalein, 185. 
Tefcra-iodo pyrrol, 183. 
Tetronal, 46, 47, 61. 



Thalllne, 64. 

Thebaine, 103, 106-109, 121. 

Theobromine, 13, 217* 

Theocine, 218. 

Theophylline, 18, 14, 217, 218, 219. 

— 8-amino-, 219. 
—- 8-chloro-, 219. 
Thermodin, 75. 
Thiocoll, 169. 

Thioglycollic acid, antimony deriva- 
tives of, 216. 
Thiosinamine, 239. 
Thymatol, 153, 163. 
Thymegol, 193. 
Thymin, 223. 
Thyminio acid, 223. 
Thymol, 153, 159, 166. 

— carbonate, 163. 
Thymol-p-sulphonic acid, mercury 

salt of, 192. 
Tiodine, 239. 
Tolamine, 180. 
Toluene, behaviour of in organism, 

39. 
p-Toiuenesulphonchloramide, 180. 
p-Toluenesulphondichloramide, 181. 
j>-To]uenesulphonyl chloride, 180. 
Toluidine, 68. 

— arsenate, 205. 
m-Tolylsemicarbazide, 67. 
Tozynone, 193. 

Traube's theory of narcosis, 48. 

Triacetin, 22, 46, 47. 

Triacetonamine, 90, 96. 

Triacetone-aJkamine-carbozylio acid, 
97. 

Triacetyl-aloXa, 227. 

Tribromaloln, 227. 

Tribromphenol, 154.. 

Tribromsalol, 55. 

Trichloracetic acid, 52. 

Trichlorphenol, 154. 

Trigemin, 54. 

Tri-iodo-meta-cresol, 184, 185. 

Trimethylamine, 106, 147. 

Trimethylamino-acetocatechol chlor- 
ide, 149. 

Trimethylamino-ethylcatechol chlor- 
ide 149 

Trional, 46, 47, 60, 61, 62. 

Trioxymethylene, 175. 

Triphenin, 74. 

Triphenylmethane dyes, 171, 172. 

Triphenyl phosphate, 164. 

Triphenylstibine sulphide, 289. 

Tropacocaine, 88, 94, 95. 

Tropeines, 86, gg, 89, 94. 

Tropic acid, 86, ^, 



250 



SYNTHETIC DRUGS 



Tropine, 86, 87. 
^.Tropine, 88, 94. 95. 
Tzopinone, 88, 94, 95. 
TruxUline, 98. 
Trypaflayine, 178-174. 
Trypan blue, 172. 

— red, 171, 172. 

Trypttin, aoMon of on drags, 37. 

Tyhnarin, 160. 

Tylnatrin, 157. 

Tyramine, 140 (see also ^-Hydroxy- 

phenylethylamine). 
Tyrosine, 12, 80, 187. 

— behaviour of in organisnl, 88. 

— ethyl ester, 148. 

Uhsatubatiov, effect of, 31-82. 

Uric acid, 219-220. 

Urol, 222. 

Urosin, 220. 

Urotropin, 176, 219, 222, 228. 

Ursal, 220. 

Uvitonic acid, 174-175. 



Vaubbiahic adds, 24, 186, 286. 

— acid deriyatiyes, 236. 
Valerobromine, 188. 
Validol, 286. 

Vanillic acid, behaviour of in organ- 
ism, 41, 42> 
VanUlin, 118. 

— behaviour of in organism, 42. 
Veratraldehyde, 119, 126, 133. 
Veratric acid, 41, 180. 
Veratrole, 20, 168. 

Veronal, 56, 57* 
Veronal-sodium, 57. 
Vesipyrin, 163. 
Vinyl-diaoetonamine, 97, 98. 
Vinyl-diacetone-alkamine, 90, 97, 98. 
Vioform, 186. 

Xakthisb, 18. 
—derivatives, 13, 217-219- 

Zing perhydrol, 190. 

— sulphanilate, 195. 



OFO 18 113^0 



PBINTBO IN GBKAT BBirAIM BT TBB UKIYEBSITT FBB8S, ABBBDBEN 



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